Vacuum mattress or long spine board: which method of spinal stabilisation in trauma patients is more time consuming? A simulation study.

BACKGROUND: Spinal stabilisation is recommended for prehospital trauma treatment. In Germany, vacuum mattresses are traditionally used for spinal stabilisation, whereas in anglo-american countries, long spine boards are preferred. While it is recommended that the on-scene time is as short as possible, even less than 10 minutes for unstable patients, spinal stabilisation is a time-consuming procedure. For this reason, the time needed for spinal stabilisation may prevent the on-scene time from being brief. The aim of this simulation study was to compare the time required for spinal stabilisation between a scoop stretcher in conjunction with a vacuum mattress and a long spine board. METHODS: Medical personnel of different professions were asked to perform spinal immobilizations with both methods. A total of 172 volunteers were immobilized under ideal conditions as well as under realistic conditions. A vacuum mattress was used for 78 spinal stabilisations, and a long spinal board was used for 94. The duration of the procedures were measured by video analysis. RESULTS: Under ideal conditions, spinal stabilisation on a vacuum mattress and a spine board required 254.4 s (95 % CI 235.6-273.2 s) and 83.4 s (95 % CI 77.5-89.3 s), respectively (p < 0.01). Under realistic conditions, the vacuum mattress and spine board required 358.3 s (95 % CI 316.0-400.6 s) and 112.6 s (95 % CI 102.6-122.6 s), respectively (p < 0.01). CONCLUSIONS: Spinal stabilisation for trauma patients is significantly more time consuming on a vacuum mattress than on a long spine board. Considering that the prehospital time of EMS should not exceed 60 minutes and the on-scene time should not exceed 30 minutes or even 10 minutes if the patient is in extremis, based on our results, spinal stabilisation on a vacuum mattress may consume more than 20 % of the recommended on-scene time. In contrast, stabilisation on a spine board requires only one third of the time required for that on a vacuum mattress. We conclude that a long spine board may be feasible for spinal stabilisation for critical trauma patients with timesensitive life threatening ABCDE-problems to ensure the shortest possible on-scene time for prehospital trauma treatment, not least if a patient has to be rescued from an open or inaccessible terrain, especially that with uneven overgrown land.

Uterine bathing with sonography gel prior to IVF/ICSI-treatment in patients with endometriosis, a multicentre randomised controlled trial.

STUDY QUESTION: What is the effect of uterine bathing with sonography gel prior to IVF/ICSI-treatment on live birth rates after fresh embryo transfer in patients with endometriosis? SUMMARY ANSWER: After formal interim analysis and premature ending of the trial, no significant difference between uterine bathing using a pharmacologically neutral sonography gel compared to a sham procedure on live birth rate after fresh embryo transfer in endometriosis patients (26.7% vs. 15.4%, relative risk (RR) 1.73, 95% confidence interval (CI) 0.81-3.72; P-value 0.147) could be found, although the trial was underpowered to draw definite conclusions. WHAT IS KNOWN ALREADY: Impaired implantation receptivity contributes to reduced clinical pregnancy rates after IVF/ICSI-treatment in endometriosis patients. Previous studies have suggested a favourable effect of tubal flushing with Lipiodol® on natural conceptions. This benefit might also be explained by enhancing implantation through endometrial immunomodulation. Although recent studies showed no beneficial effect of endometrial scratching, the effect of mechanical stress by intrauterine infusion on the endometrium in endometriosis patients undergoing IVF/ICSI-treatment has not been investigated yet. STUDY DESIGN SIZE DURATION: We performed a multicentre, patient-blinded, randomised controlled trial in which women were randomly allocated to either a Gel Infusion Sonography (GIS, intervention group) or a sham procedure (control group) prior to IVF/ICSI-treatment. Since recruitment was slow and completion of the study was considered unfeasible, the study was halted after inclusion of 112 of the planned 184 women. PARTICIPANTS/MATERIALS SETTING METHODS: We included infertile women with surgically confirmed endometriosis ASRM stage I-IV undergoing IVF/ICSI-treatment. After informed consent, women were randomised to GIS with intrauterine instillation of ExEm-gel® or sonography with gel into the vagina (sham). This was performed in the cycle preceding the embryo transfer, on the day GnRH analogue treatment was started. The primary endpoint was live birth rate after fresh embryo transfer. Analysis was performed by both intention-to-treat and per-protocol. MAIN RESULTS AND THE ROLE OF CHANCE: Between July 2014 to September 2018, we randomly allocated 112 women to GIS (n = 60) or sham procedure (n = 52). The live birth rate after fresh embryo transfer was 16/60 (26.7%) after GIS versus 8/52 (15.4%) after the sham (RR 1.73, 95% CI 0.81-3.72; P-value 0.147). Ongoing pregnancy rate was 16/60 (26.7%) after GIS versus 9/52 (17.3%) in the controls (RR 1.54, 95% CI 0.74-3.18). Miscarriage occurred in 1/60 (1.7%) after GIS versus 5/52 (9.6%) in the controls (RR 0.17, 95% CI 0.02-1.44) women. Uterine bathing resulted in a higher pain score compared with a sham procedure (visual analogue scale score 2.7 [1.3-3.5] vs. 1.0 [0.0-2.0], P < 0.001). There were two adverse events after GIS compared with none after sham procedures. LIMITATIONS REASONS FOR CAUTION: The study was terminated prematurely due to slow recruitment and trial fatigue. Therefore, the trial is underpowered to draw definite conclusions regarding the effect of uterine bathing with sonography gel on live birth rate after fresh embryo transfer in endometriosis patients undergoing IVF/ICSI-treatment. WIDER IMPLICATIONS OF THE FINDINGS: We could not demonstrate a favourable effect of uterine bathing procedures with sonography gel prior to IVF/ICSI-treatment in patients with endometriosis. STUDY FUNDING/COMPETING INTERESTS: Investigator initiated study. IQ Medical Ventures provided the ExEm FOAM® kits free of charge, they were not involved in the study design, data management, statistical analyses and/or manuscript preparation, etc. C.B.L. reports receiving grants from Ferring, Merck and Guerbet, outside the submitted work. C.B.L. is Editor-in-Chief of Human Reproduction. V.M. reports grants and other from Guerbet, outside the submitted work. B.W.M. reports grants from NHMRC (GNT1176437), personal fees from ObsEva, Merck and Merck KGaA, Guerbet and iGenomix, outside the submitted work. N.P.J. reports research funding from Abb-Vie and Myovant Sciences and consultancy for Vifor Pharma, Guerbet, Myovant Sciences and Roche Diagnostics, outside the submitted work. K.D. reports personal fees from Guerbet, outside the submitted work. The other authors do not report any conflicts of interest. No financial support was provided. TRIAL REGISTRATION NUMBER: NL4025 (NTR4198). TRIAL REGISTRATION DATE: 7 October 2013. DATE OF FIRST PATIENT'S ENROLMENT: 22 July 2014.

Continuous oral contraceptives versus long-term pituitary desensitization prior to IVF/ICSI in moderate to severe endometriosis: study protocol of a non-inferiority randomized controlled trial.

STUDY QUESTIONS: The primary objective is to investigate if continuous use of oral contraceptives is non-inferior compared to long-term pituitary desensitization with a GnRH agonist prior to IVF/ICSI in patients with moderate to severe endometriosis with regard to treatment efficacy. Secondary objectives concern treatment safety and cost-effectiveness. WHAT IS KNOWN ALREADY: Long-term pituitary desensitization with a GnRH agonist for 3-6 months prior to IVF/ICSI improves clinical pregnancy rates in women suffering from endometriosis. However, discussion about this treatment strategy exists because of its uncomfortable side effects. Alternatively, IVF/ICSI pre-treatment with continuously administered oral contraceptives may offer fewer side-effects and lower (in)direct costs, as well as encouraging IVF outcomes in women with endometriosis. To date, these two different IVF/ICSI pre-treatment strategies in women with endometriosis have not been directly compared. STUDY DESIGN SIZE DURATION: An open-label, parallel two-arm randomized controlled multicenter trial is planned, including patients with moderate to severe endometriosis. To demonstrate an absolute difference of 13% (delta of 10% with non-inferiority margin of 3%) with a power of 80% 137 patients per group are sufficient. Taking into account a withdrawal of patients of 10% and a cancelation rate of embryo transfer after ovarian pick up of 10% (for instance due to fertilization failure), the sample size calculation is rounded off to 165 patients per group; 330 patients in total will be included. After informed consent, eligible patients will be randomly allocated to the intervention or reference group by using web based block randomization stratified per centre. Study inclusion is expected to be complete in 3-5 years. PARTICIPANTS/MATERIALS SETTING METHODS: The research population consists of patients with moderate to severe endometriosis (ASRM III/IV) who are scheduled for their first, second or third IVF/ICSI treatment attempt. Women aged over 41 years, younger than 18 years, with a known contraindication for the use of oral contraceptives and/or GnRH agonists or with severe male factor infertility will be excluded from participation. After informed consent patients are allocated to the intervention group (one-phase oral contraceptive continuously during three subsequent months) or the reference group (three Leuprorelin 3.75 mg i.m./s.c. depot injections during three subsequent months). Tibolon 2.5 mg can be given daily as add-back therapy in the reference group. After 3 months of pre-treatment the IVF/ICSI stimulation phase will be started. The primary outcome is live birth rate after fresh embryo transfer. Secondary outcomes are cumulative live birth rate after one IVF/ICSI treatment cycle (including fresh and frozen embryo transfers up to 15 months after randomization), ongoing pregnancy rate and time to pregnancy. In addition, treatment outcome parameters, adverse events, side-effects during the first 3 months, complications, recurrence of endometriosis (complaints), quality of life, patient preferences, safety and costs effectiveness will be reported. Measurements will be performed at baseline and at 3, 6, 9, 12 and 15 months after randomization. STUDY FUNDING/COMPETING INTERESTS: All authors have no conflict of interest related to this manuscript. The department of reproductive medicine of the Amsterdam UMC location VUmc has received several research and educational grants from Guerbet, Merck and Ferring not related to the submitted work. TRIAL REGISTRATION NUMBER: The trial is registered as the COPIE trial (Continuous use of Oral contraceptives as an alternative for long-term Pituitary desensitization with a GnRH agonist prior to IVF/ICSI in Endometriosis patients) in the Dutch Trial Register (Ref. No. NTR6357, http://www.trialregister.nl). TRIAL REGISTRATION DATE: 16 March 2017. DATE OF FIRST PATIENT'S ENROLMENT: Enrollment is planned for November 2018.

Transanal minimally invasive rectal resection for deep endometriosis: a promising technique.

AIM: Surgical management of patients with deep endometriosis (DE) of the rectum is difficult. Inflammation and subsequent adhesions due to DE impede access to the lower pelvis and may lead to complications during laparoscopic low anterior resection (LAR). Transanal minimally invasive surgery (TAMIS) is an alternative to an abdominal approach with potential advantages. The aim of this study was to provide a description of the TAMIS technique and to present the perioperative results of TAMIS and of conventional LAR in patients with DE. METHOD: A prospective consecutive cohort of patients undergoing rectal resection for DE had either conventional laparoscopic LAR or TAMIS rectal excision. Pre-, intra- and postoperative parameters, such as patient symptomatology, operating time and postoperative complications were compared between the groups. Quality of life was assessed using the EORTC-QLQ-29/30 questionnaires. RESULTS: Between May 2014 and March 2016 a total of 11 rectal resections were performed, including five TAMIS procedures. No differences were found in the pre-, intra- or postoperative parameters. Two major complications occurred after conventional LAR and none after TAMIS. No differences in quality of life were found between the groups. CONCLUSION: Transanal minimally invasive surgery for DE of the rectum is feasible. Potential advantages include better surgical access to the pelvis, possibly fewer complications than LAR and no extraction incision with no difference in quality of life. Larger prospective studies are required to compare TAMIS with conventional rectal resection.

Pressure-standardised mammography does not affect visibility, contrast and sharpness of stable lesions.

INTRODUCTION: A recent technological development allows pressure-standardised mammography by personalizing the compression force to the breast size and firmness. The technique has been shown to reduce pain and compression variability between consecutive exams, but also results in a slightly thicker compressed breast during exposure. This raises the question whether visibility, contrast and sharpness of lesions are affected? METHODS: Four experienced radiologists compared 188 stable lesions and structures including (clusters of) calcifications, (oil) cysts and lymph nodes that were visible in mammograms obtained in 2009 with a pain-tolerance limited 18 daN target force compression protocol, and in 2014/2015 obtained with a 10kPa (75mmHg) pressure-standardised compression protocol. Observers were blinded for all DICOM metadata and rated which of the randomly ordered, side by side presented images had better lesion visibility, contrast and sharpness, or whether they saw no difference. They also indicated which overall image they preferred, if any, and whether the non-preferred image was still adequate. Statistical non-inferiority is concluded when the lower limit of the 95% confidence interval of the 4-rater averaged 'new protocol better' proportions exceed the non-inferiority limit of 0.463. RESULTS: In 2014/2015, the compressions were significantly milder, with on average 17% (mediolateral oblique) to 29% (craniocaudal) lower forces. Breasts remained on average 2.4% (1.4mm) thicker. Dose was significantly lower (6.5%), which is explained by glandular atrophy. The 95% confidence interval lower limits are 0.479 for visibility, 0.473 for contrast, 0.488 for sharpness and 0.486 for preference, all exceeding the non-inferiority limit. Of the 60 non-preferred mammograms, multiple observers found only five to be inadequate: 4 obtained with the force protocol and 1 with the pressure protocol. CONCLUSION: Pain-reduced mammography with 10kPa pressure-standardised compression has non-inferior visibility, contrast and sharpness for stable lesions compared to pain-tolerance limited 18daN target force compression.

Laparoscopic Imaging Techniques in Endometriosis Therapy: A Systematic Review.

Endometriosis is a common disease associated with pelvic pain and subfertility. Laparoscopic surgical treatment has proven effective in endometriosis, but is hampered by a high rate of recurrence. The aim of this systematic review was to evaluate the intraoperative identification of endometriosis by enhanced laparoscopic imaging techniques, focusing on sensitivity and specificity. A systematic review was conducted according to PRISMA guidelines in PubMed, Embase, Cochrane Library, and Web of Science. Published prospective studies reporting on enhanced laparoscopic imaging techniques during endometriosis surgery were included. General study characteristics and reported outcomes, including sensitivity and specificity, were extracted. Nine studies were eligible for inclusion. Three techniques were described: 5-ALA fluorescence (5-ALA), autofluorescence (AFI), and narrow-band imaging (NBI). The reported sensitivity of 5-ALA and AFI for identifying endometriosis ranged from 91% to 100%, compared with 48% to 69% for conventional white light laparoscopy (WL). A randomized controlled trial comparing NBI + WL with WL alone reported better sensitivity of NBI (100% vs 79%; p < .001). All 9 studies reported an enhanced detection rate of endometriotic lesions with enhanced imaging techniques. Enhanced imaging techniques are a promising additive for laparoscopic detection and treatment of endometriosis. The 5-ALA, AFI, and NBI intraoperative imaging techniques had a better detection rate for peritoneal endometriosis compared with conventional WL laparoscopy. None of the studies reported clinical data regarding outcomes. Future studies should address long-term results, such as quality of life, recurrence, and need for reoperation.

Hysteroscopic proximal tubal occlusion versus laparoscopic salpingectomy as a treatment for hydrosalpinges prior to IVF or ICSI: an RCT.

STUDY QUESTION: Does hysteroscopic proximal tubal occlusion by intratubal devices as a treatment for hydrosalpinges result in comparable ongoing pregnancy rates following IVF/ICSI when compared with laparoscopic salpingectomy? SUMMARY ANSWER: Hysteroscopic proximal tubal occlusion by intratubal devices is inferior to laparoscopic salpingectomy in the treatment of hydrosalpinges in women undergoing IVF/ICSI with respect to ongoing pregnancy rates. WHAT IS KNOWN ALREADY: It is known that women with hydrosalpinges undergoing IVF have poorer pregnancy outcomes compared with women with other forms of tubal infertility. In these women, both laparoscopic salpingectomy and laparoscopic proximal tubal ligation are known to improve IVF outcomes. At present, it is unclear whether a less-invasive hysteroscopic treatment with intratubal devices leads to similar ongoing pregnancy rates following IVF when compared with laparoscopic salpingectomy. STUDY DESIGN, SIZE, DURATION: A two-centre, randomized, controlled, non-inferiority trial. Between October 2009 and December 2014 a total of 85 women were included in this study; of whom, 42 were randomized to hysteroscopic proximal occlusion by intratubal device placement and 43 were randomized to laparoscopic salpingectomy. Randomization was based on a computer-generated randomization list. The study was unblinded. The primary outcome was ongoing pregnancy rate, defined as a fetal heartbeat on ultrasound beyond 10-week gestation following one IVF/ICSI treatment (fresh and frozen-thawed embryo transfers). PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied women aged 18-41 years, with uni- or bilateral ultrasound visible hydrosalpinges who were scheduled for an IVF/ICSI treatment. MAIN RESULTS AND THE ROLE OF CHANCE: The ongoing pregnancy rates per patient according to the intention-to-treat principle were 11/42 (26.2%) after hysteroscopic proximal occlusion by intratubal devices (intervention group) versus 24/43 (55.8%) after laparoscopic salpingectomy (control group) (P = 0.008) [absolute difference: 26.1%; 95% confidence interval (CI): 0.5-51.7, relative risk (RR): 0.56; 95% CI: 0.31-1.03, P = 0.01]. In the per protocol analysis, the ongoing pregnancy rate per patient following hysteroscopic proximal occlusion by intratubal devices was 9/27 (33.3%) compared with 19/32 (59.4%) following laparoscopic salpingectomy (P = 0.067) (absolute difference: 29.6%; 95% CI: 7.1 to 49.1, RR: 0.47; 95% CI: 0.27-0.83, P = 0.062). LIMITATIONS, REASONS FOR CAUTION: Masking participants and investigators would be difficult due to the nature of both interventions. Since we had objective outcome measurements, we withheld sham procedures, leaving the study unblinded. Furthermore, our low sample size resulted in wide CIs. A larger sample size would result in a more accurate treatment effect; however, this was non-feasible for recruitment and inclusion. WIDER IMPLICATIONS OF THE FINDINGS: In the treatment of hydrosalpinges prior to IVF/ICSI, hysteroscopic proximal occlusion by intratubal devices is inferior to laparoscopic salpingectomy. STUDY FUNDING/COMPETING INTERESTS: The intratubal devices were received from Conceptus, Inc., San Carlos, CA, USA, which was acquired by Bayer HealthCare Pharmaceuticals, Inc., Whippany, NJ, USA in 2013. Conceptus, Inc./Bayer HealthCare Pharmaceuticals, Inc. had no role in the study design, data collection and analyses, decision to publish or preparation of the manuscript. The study as a whole was funded by the SWOG (foundation for scientific investigation in obstetrics and gynaecology of the VU University Medical Centre, Amsterdam, the Netherlands). P.G.A.H. has received non-financial support from Conceptus, Inc. during the conduct of this study. He has received grants from Ferring B.V., Merck Serono and Abbott outside the submitted work. M.H.E. has received personal fees from Smith and Nephew and IQ Medical Ventures outside the submitted work. TRIAL REGISTRATION NUMBER: The Dutch Trial Register: NTR 2073. TRIAL REGISTRATION DATE: October 21, 2009. DATE OF FIRST PATIENT'S ENROLMENT: October 26, 2009.

Force balancing in mammographic compression.

PURPOSE: In mammography, the height of the image receptor is adjusted to the patient before compressing the breast. An inadequate height setting can result in an imbalance between the forces applied by the image receptor and the paddle, causing the clamped breast to be pushed up or down relative to the body during compression. This leads to unnecessary stretching of the skin and other tissues around the breast, which can make the imaging procedure more painful for the patient. The goal of this study was to implement a method to measure and minimize the force imbalance, and to assess its feasibility as an objective and reproducible method of setting the image receptor height. METHODS: A trial was conducted consisting of 13 craniocaudal mammographic compressions on a silicone breast phantom, each with the image receptor positioned at a different height. The image receptor height was varied over a range of 12 cm. In each compression, the force exerted by the compression paddle was increased up to 140 N in steps of 10 N. In addition to the paddle force, the authors measured the force exerted by the image receptor and the reaction force exerted on the patient body by the ground. The trial was repeated 8 times, with the phantom remounted at a slightly different orientation and position between the trials. RESULTS: For a given paddle force, the obtained results showed that there is always exactly one image receptor height that leads to a balance of the forces on the breast. For the breast phantom, deviating from this specific height increased the force imbalance by 9.4 ± 1.9 N/cm (6.7%) for 140 N paddle force, and by 7.1 ± 1.6 N/cm (17.8%) for 40 N paddle force. The results also show that in situations where the force exerted by the image receptor is not measured, the craniocaudal force imbalance can still be determined by positioning the patient on a weighing scale and observing the changes in displayed weight during the procedure. CONCLUSIONS: In mammographic breast compression, even small changes in the image receptor height can lead to a severe imbalance of the applied forces. This may make the procedure more painful than necessary and, in case the image receptor is set too low, may lead to image quality issues and increased radiation dose due to undercompression. In practice, these effects can be reduced by monitoring the force imbalance and actively adjusting the position of the image receptor throughout the compression.

Influence of segmented vessel size due to limited imaging resolution on coronary hyperemic flow prediction from arterial crown volume.

Computational predictions of the functional stenosis severity from coronary imaging data use an allometric scaling law to derive hyperemic blood flow (Q) from coronary arterial volume (V), Q = αV(ß) Reliable estimates of α and ß are essential for meaningful flow estimations. We hypothesize that the relation between Q and V depends on imaging resolution. In five canine hearts, fluorescent microspheres were injected into the left anterior descending coronary artery during maximal hyperemia. The coronary arteries of the excised heart were filled with fluorescent cast material, frozen, and processed with an imaging cryomicrotome to yield a three-dimensional representation of the coronary arterial network. The effect of limited image resolution was simulated by assessing scaling law parameters from the virtual arterial network at 11 truncation levels ranging from 50 to 1,000 µm segment radius. Mapped microsphere locations were used to derive the corresponding relative Q using a reference truncation level of 200 µm. The scaling law factor α did not change with truncation level, despite considerable intersubject variability. In contrast, the scaling law exponent ß decreased from 0.79 to 0.55 with increasing truncation radius and was significantly lower for truncation radii above 500 µm vs. 50 µm (P< 0.05). Hyperemic Q was underestimated for vessel truncation above the reference level. In conclusion, flow-crown volume relations confirmed overall power law behavior; however, this relation depends on the terminal vessel radius that can be visualized. The scaling law exponent ß should therefore be adapted to the resolution of the imaging modality.

High cumulative risk of intussusception in patients with Peutz-Jeghers syndrome: time to update surveillance guidelines?

OBJECTIVES: Peutz-Jeghers syndrome (PJS) is characterized by gastrointestinal hamartomas. The hamartomas are located predominantly in the small intestine and may cause intussusceptions. We aimed to assess the characteristics, risk, and onset of intussusception in a large cohort of PJS patients to determine whether enteroscopy with polypectomy should be incorporated into surveillance recommendations. METHODS: All PJS patients from two academic hospitals were included in this cohort study (prospective follow-up between 1995 and July 2009). We obtained clinical data by interview and chart review. Deceased family members with PJS were included retrospectively. Cumulative intussusception risks were calculated by Kaplan­Meier analysis. RESULTS: We included 110 PJS patients (46% males) from 50 families. In all, 76 patients (69%) experienced at least one intussusception (range 1-6), at a median age of 16 (3-50) years at first occurrence. The intussusception risk was 50% at the age of 20 years (95% confidence interval 17-23 years) and the risk was independent of sex, family history, and mutation status. The intussusceptions occurred in the small intestine in 95% of events, and 80% of all intussusceptions (n=128) presented as an acute abdomen. Therapy was surgical in 92.5% of events. Based on 37 histology reports, the intussusceptions were caused by polyps with a median size of 35 mm (range 15-60 mm). CONCLUSIONS: PJS patients carry a high cumulative intussusception risk at young age. Intussusceptions are generally caused by polyps >15 mm and treatment is mostly surgical. These results support the approach of enteroscopic surveillance, with removal of small-intestinal polyps >10-15 mm to prevent intussusceptions. The effect of such an approach on the incidence of intussusception remains to be established in prospective trials.

Quality of life and psychological distress in patients with Peutz-Jeghers syndrome.

Little is known about psychological distress and quality of life (QoL) in patients with Peutz-Jeghers syndrome (PJS), a rare hereditary disorder. We aimed to assess QoL and psychological distress in PJS patients compared to the general population, and to evaluate determinants of QoL and psychological distress in a cross-sectional study. PJS patients completed a questionnaire on QoL, psychological distress, and illness perceptions. The questionnaire was returned by 52 patients (85% response rate, 56% females, median age 44.5 years). PJS patients reported similar anxiety (p = 0.57) and depression (p = 0.61) scores as the general population. They reported a lower general health perception (p = 0.003), more limitations due to emotional problems (p = 0.045) and a lower mental well-being (p = 0.036). Strong beliefs in negative consequences of PJS on daily life, a relapsing course of the disease, strong emotional reactions to PJS, and female gender were major determinants for a lower QoL. PJS patients experience a similar level of psychological distress as the general population, but a poorer general health perception, more limitations due to emotional problems, and a poorer mental QoL. Illness perceptions and female gender were major predictors for this lower QoL. These results may help to recognize PJS patients who might benefit from psychological support.

High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations.

OBJECTIVES: Peutz-Jeghers syndrome (PJS) is an autosomal dominant inherited disorder associated with increased cancer risk. Surveillance and patient management are, however, hampered by a wide range in cancer risk estimates. We therefore performed a systematic review to assess cancer risks in PJS patients and used these data to develop a surveillance recommendation. METHODS: A systematic PubMed search was performed up to February 2009, and all original articles dealing with PJS patients with confirmed cancer diagnoses were included. Data involving cancer frequencies, mean ages at cancer diagnosis, relative risks (RRs), and cumulative risks were collected. RESULTS: Twenty-one original articles, 20 cohort studies, and one meta-analysis fulfilled the inclusion criteria. The cohort studies showed some overlap in the patient population and included a total of 1,644 patients; 349 of them developed 384 malignancies at an average age of 42 years. The most common malignancy was colorectal cancer, followed by breast, small bowel, gastric, and pancreatic cancers. The reported lifetime risk for any cancer varied between 37 and 93%, with RRs ranging from 9.9 to 18 in comparison with the general population. Age-related cumulative risks were given for any cancer and gastrointestinal, gynecological, colorectal, pancreatic, and lung cancers. CONCLUSIONS: PJS patients are markedly at risk for several malignancies, in particular gastrointestinal cancers and breast cancer. On the basis of these elevated risks, a surveillance recommendation is developed to detect malignancies in an early phase and to remove polyps that may be premalignant and may cause complications, so as to improve the outcome.

Adhesive surface determines raft composition in platelets adhered under flow.

Adhesion to von Willebrand factor (VWF) induces platelet spreading, whereas adhesion to collagen induces aggregation. Here we report that cholesterol-rich domains (CRDs) or rafts play a critical role in clustering of receptors that control these responses. Platelets adhered to VWF and collagen show CRDs concentrated in filopodia which contain both the VWF receptor glycoprotein (GP) Ibalpha and the collagen receptor GPVI. Biochemical analysis of CRDs shows a threefold enrichment of GPIbalpha (but not GPVI) in VWF-adhered platelets and a fourfold enrichment of GPVI (but not GPIbalpha) in collagen-adhered platelets. Depletion of cholesterol (i) leaves the initial adhesion unchanged, (ii) inhibits spreading on VWF and aggregate formation on collagen, (iii) leaves filopodia formation intact, and (iv) reduces the localization in filopodia of GPIbalpha but not of GPVI. These data show that the adhesive substrate determines the composition of CRDs, and that cholesterol is crucial for redistribution of GPIbalpha but not of GPVI.

Cytokeratin phenotyping does not help in distinguishing oesophageal adenocarcinoma from cancer of the gastric cardia.

BACKGROUND: It is sometimes difficult to distinguish between cardia cancer and oesophageal cancer. AIMS: To evaluate whether cytokeratin (CK) expression of the tumour can be of value in differentiating between the two tumour types. METHODS: Consecutive patients with a malignant tumour in the oesophagus or stomach were recruited. Biopsy specimens were taken for routine haematoxylin and eosin staining. One tissue block with representative tissue was selected for immunohistochemical staining (CK7 and CK20). RESULTS: Endoscopically located adenocarcinoma of the oesophagus was present in 84 patients (64 men, 20 women; mean age, 68 years; range, 44-91). Cancer located primarily in the gastric cardia was present in 63 patients (42 men, 21 women; mean age, 68 years; range, 42-88). The histological diagnosis was metastasis from a primary tumour outside the oesophagus or stomach in 19 patients. The patients were divided into three groups for the immunohistochemical analysis. Patients in group A had definite oesophageal cancer, group B patients had a definite carcinoma located in the gastric cardia, and group C patients had an obstructing tumour distal in the oesophagus at the level of the diaphragm, which could not be passed with the endoscope. Paraffin wax embedded material was available from 122 patients for immunostaining and CK analysis. There was no significant difference in expression or distribution of CK7 or CK20 in the three groups of patients. CONCLUSION: CK phenotyping cannot distinguish between cancer arising from a Barrett's oesophagus and carcinoma originating in the gastric cardia.

A tripeptide mimetic of von Willebrand factor residues 981-983 enhances platelet adhesion to fibrinogen by signaling through integrin alpha(IIb)beta3.

BACKGROUND: RGD is a major recognition sequence for ligands of platelet alpha(IIb)beta3. OBJECTIVE AND METHODS: To identify potential binding sites for alpha(IIb)beta3 apart from RGD, we screened phage display libraries by blocking the enrichment of RGD-containing phages with a GRGDS peptide and identified a novel integrin recognition tripeptide sequence, VPW. RESULTS: Platelets adhered to an immobilized cyclic VPW containing peptide in a alpha(IIb)beta3-dependent manner; platelets and alpha(IIb)beta3-expressing CHO cells adhered faster to immobilized alpha(IIb)beta3-ligands in the presence of soluble VPW. In platelets adhering to fibrinogen, VPW accelerated the activation of the tyrosine kinase Syk which controls cytoskeletal rearrangements. In alpha(IIb)beta3-expressing CHO cells, VPW induced a faster formation of stress fibers. Sequence alignment positioned VPW to V980-P981-W982 in the von Willebrand factor (vWf) A-3 domain. In blood from a vWf-deficient individual, VPW increased platelet adhesion to fibrinogen but not to collagen under flow and rescued the impaired adhesion to vWf deficient in A-3. CONCLUSION: These data reveal a VPW sequence that contributes to alpha(IIb)beta3 activation in in vitro experiments. Whether the V980-P981-W982 sequence in vWf shows similar properties under in vivo conditions remains to be established.

Concentration of rafts in platelet filopodia correlates with recruitment of c-Src and CD63 to these domains.

The molecular mechanism that causes non-adhesive, discoid platelets to transform into sticky dendritic bodies that form blood clumps is a complex series of events. Recently it has become clear that lipid microdomains--also known as rafts--play a crucial role in this process. We have used a non-cytolytic derivative of perfringolysin-O, a cholesterol binding cytolysin, that binds selectively to cholesterol-rich membrane domains, combined with confocal- and immunoelectron microscopy to visualize cholesterol-raft dynamics during platelet adhesion. In resting platelets cholesterol was uniformly distributed on the cell surface and confined to distinct intracellular compartments (i.e. multivesicular bodies, dense granules, and the internal membranes of alpha-granules). Upon interaction with fibrinogen, cholesterol accumulated at the tips of filopodia and at the leading edge of spreading cells. Stimulation with thrombin receptor activating peptide (TRAP) resulted in a similar redistribution of cholesterol towards filopodia. The adhesion-dependent raft aggregation was accompanied by concentration of the tyrosine kinase c-Src and the tetraspanin CD63 in these domains, whereas glycoprotein Ib (GPIb) was not selectively targeted to the raft clusters. c-Src, the tetraspanin CD63, and GPIb were recovered in biochemically isolated low-density membrane fractions. Disruption of rafts by depleting membrane cholesterol had no effect on platelet shape change but inhibited platelet spreading on fibrinogen and TRAP-induced aggregation. Our results demonstrate that cholesterol rafts in platelets are dynamic entities in the membrane that co-cluster with the tyrosine kinase c-Src and the costimulatory molecule CD63 in specialized domains at the cell surface, thereby providing a possible mechanism in functioning as signaling centres.

Genetic alterations of chromosome 17 in human breast carcinoma studied by fluorescence in situ hybridization and molecular DNA techniques.

Fluorescence in situ hybridization (FISH) with a chromosome 17 centromere-specific probe was used together with Southern blot analyses and PCR amplification of a polymorphic segment to characterize 13 breast carcinomas. Cells with an abnormal number of chromosome 17 centromeres were found mixed with disomic cells in nine of the 13 tumors studied. Three of the four cases found to have a normal number of chromosome 17 centromeres had DNA alterations restricted to allelic imbalance of the two most distal markers on 17p; the fourth had no detectable alterations. In contrast, of the seven tumors found to have genetic alterations elsewhere on chromosome 17, all had more than one cell population when examined for numerical chromosome 17 alterations. The present data support the hypothesis that alterations at the distal short arm of chromosome 17 represent earlier events in the tumorigenic process than do the other chromosome 17 abnormalities observed. The results of molecular DNA studies interpreted as allelic imbalance of distal 17p markers in most cases probably reflect chromosomal rearrangements like loss of specific loci, rather than monosomies and large deletions. The report illustrates the usefulness of FISH when added to current molecular DNA techniques.

High resolution chromosome banding in search of germ line mutations applied on testicular cancer patients.

Patients with bilateral and/or familial testicular cancer are assumed to demonstrate germ line mutations if such mutations are instrumental in testicular cancer patients. Constitutional rearrangements have to our knowledge not been reported, while an increased level of constitutional chromosome instability has been claimed. Lymphocytes from 12 Norwegian patients with bilateral or familial testicular cancer have been studied by high resolution Giemsa banding. A possible germ line mutation would be expected to be seen in every cell. It is therefore sufficient to examine one pair of the individual chromosomes obtained, if necessary, from several cells. Based on our previous findings of loss of heterozygosity in the chromosome regions 3p and 11p in testicular tumors, these chromosome arms were paid special attention. However, no mutations were observed in these regions nor in any other chromosome. Applying a 95% confidence interval, we conclude that less than 23% of familial and/or bilateral testicular cancer patients are caused by germ line mutations large enough to be detected with high resolution banding of at least 450 G-bands per haploid genome. The presented analyses were used to standardize the resolution determination in our laboratory.

Influence of ozone air pollution on plant-herbivore interactions. Part 2: Effects of ozone on feeding preference, growth and consumption rates of monarch butterflies (Danaus plexippus).

Effects of ozone fumigation of Asclepias curassavica L. and A. syriaca L. on feeding preference, growth, development, and nutritional indices of monarch larvae were investigated in conjunction with changes in specific leaf metabolites. While foliar chemistry was quite variable, fumigation generally decreased sugars and proteins, and increased amino acids and phenolics in A. curassavica. Effects were similar in A. syriaca except that sugars were generally increased while amino acids were usually not affected. On A. curassavica, 3rd instar larvae preferred ozone-treated leaves while 4th instars showed no preference; conversely, on A. syriaca, 3rd instars showed no preference while 4th instars preferred control leaves. Relative growth rate and relative consumption rate of 5th instars were greater on fumigated plants of both species, but other nutritional indices were unaffected. Larvae developed more rapidly on intact fumigated plants of both species than on the respective controls. The results suggest that enhanced feeding stimulation may be the primary cause of the altered behavior and performance on ozone-fumigated plants.

Influence of ozone air pollution on plant-herbivore interactions. Part 1: Biochemical changes in ornamental milkweed (Asclepias curassavica L.; asclepiadaceae) induced by ozone.

A series of fumigation experiments was conducted with bloodflower (Asclepias curassavica L.) in continuous-flow stirred reactors (CSTRs) to elucidate the effects of ozone on foliar concentrations of several primary and secondary plant metabolites relevant to herbivores. Plants 8 weeks of age were subjected to different ozone levels ranging from 0 to 134 nl liter(-1) for exposure periods up to 16 days. Leaves were analyzed for concentration of soluble carbohydrates, starch, free amino acids, soluble protein, total phenolics, and total cardenolides. Significant interactions between the linear effects of ozone concentration and exposure time were found for soluble carbohydrates, amino acids, cardenolides and phenolics. No significant treatment effects could be observed on foliar starch and protein concentration. The metabolic responses of plants to fumigation appeared to be altered by overall plant nutrition. It is possible that the metabolic changes observed in the host plant represent important changes in nutritional quality to insects.