Self-reported levels of education and disability progression in multiple sclerosis.

OBJECTIVES: The purpose of our study is to investigate whether socioeconomic indicators such as education, financial concerns, employment, and living status are associated with disease progression in relapsing-onset and progressive-onset Multiple Sclerosis (MS). MATERIALS AND METHODS: We performed a cross-sectional survey among individuals with MS, registered by the Flemish MS society and included socioeconomic indicators. A Cox proportional hazard regression was performed with the time from MS onset and from birth to reach an ambulatory disability milestone corresponding to Expanded Disability Status Scale (EDSS) 6 (requiring a cane) as outcome measure, adjusted for gender, age at MS onset, and immunomodulatory treatment. RESULTS: Among the participants with relapsing-onset MS, subjects reporting education for more than 12 years had a reduced risk of reaching EDSS 6 compared to subjects reporting education for less than 12 years [HR from onset 0.68 (95% CI 0.49-0.95); HR from birth 0.71 (95% CI 0.51-0.99)]. In progressive-onset MS, longer education was associated with an increased hazard to reach EDSS 6 [HR from onset 1.25 (95% CI 0.91-1.70); HR from birth 1.39 (95% CI 1.02-1.90)]. CONCLUSIONS: Our study shows an association of self-reported levels of education with disability progression in MS, with the highest level being protective in relapsing-onset MS.

How successful is TESE-ICSI in couples with non-obstructive azoospermia?

STUDY QUESTION: What are the chances of a couple with infertility due to non-obstructive azoospermia (NOA) having their genetically own child by testicular sperm extraction combined with ICSI (TESE-ICSI)? SUMMARY ANSWER: Candidate TESE-ICSI patients with NOA should be counselled that, when followed-up longitudinally, only a minority (13.4%) of men embarking for TESE eventually become a biological father. WHAT IS KNOWN ALREADY: Data available in the literature are only fragmentary because they report either on sperm retrieval rates after TESE or on the outcome of ICSI once testicular spermatozoa has been obtained, mostly in a selected subpopulation. Unfortunately, reliable data to counsel men with NOA on their chance to become a biological father are still lacking. STUDY DESIGN, SIZE, DURATION: This is a retrospective cohort study performed in the Centre for Reproductive Medicine, University Hospital of Brussel, approved by the institutional review board of the hospital. PARTICIPANTS/MATERIALS, SETTING AND METHODS: We identified all patients with NOA, based on histology, who had their first testicular biopsy between 1994 and 2009. Patients were followed longitudinally during consecutive ICSI cycles with testicular sperm. The primary outcome measure was live birth delivery. The cumulative live birth delivery rate was calculated, based only on ICSI cycles with testicular sperm (fresh and/or frozen) available for injection. When patients delivered after transfer of supernumerary frozen embryos, this delivery was tallied up to the (unsuccessful) original fresh ICSI cycle. The sperm retrieval rate and pregnancy rate were secondary outcome measures. MAIN RESULTS AND THE ROLE OF CHANCE: Among the 714 men with NOA, 40.5% had successful sperm retrieval at their first TESE. In total, 261 couples had 444 ICSI cycles and 48 frozen embryo transfer cycles, leading to 129 pregnancies and 96 live birth deliveries. Crude and expected cumulative delivery rates after six ICSI cycles were 37 and 78%. LIMITATIONS AND REASON FOR CAUTION: A retrospective cohort study design was the only way to study the cumulative delivery rate after TESE-ICSI in couples with NOA. Intrinsic limitations are related to the observational study design. WIDER IMPLICATION OF THE FINDING: TESE-ICSI is a breakthrough in the treatment of infertility due to NOA, with almost 4 out of 10 (37%) couples having ICSI obtaining a delivery. However, unselected candidate NOA patients should be counselled, before undergoing TESE, that only one out of seven men (13.4%) eventually father their genetically own child. STUDY FUNDING AND COMPETING INTERESTS: None declared.

The type of culture medium and the duration of in vitro culture do not influence birthweight of ART singletons.

STUDY QUESTION: Does the type of in vitro culture medium or the duration of in vitro culture influence singleton birthweight after IVF/ICSI treatment? SUMMARY ANSWER: In a comparison of two culture media, neither the medium nor the duration of culture (Day 3 versus Day 5 blastocyst transfer) had any effect on mean singleton birthweight. WHAT IS KNOWN ALREADY: Previous studies indicated that in vitro culture of human embryos may affect birthweight of live born singletons. Both the type of culture medium and the duration of culture may be implicated. However, these studies are small and report conflicting results. STUDY DESIGN, SIZE, DURATION: A large retrospective analysis was performed including all singleton live births after transferring fresh Day 3 or Day 5 embryos. IVF and ICSI cycles performed between April 2004 and December 2009 at a tertiary care centre were included for analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 2098 singleton live births resulting from singleton pregnancies were included for analysis. Two different sequential embryo culture media were concurrently used in an alternating way: Medicult (n = 1388) and Vitrolife (n = 710). Maternal age, maternal and paternal BMI, maternal parity, maternal smoking, main cause of infertility, cycle rank, stimulation protocol, method of fertilization (IVF or ICSI), time in culture and number of embryos transferred were taken into account. Embryo transfers were performed either on Day 3 (n = 1234) or on Day 5 (n = 864). Singleton birthweight was the primary outcome parameter. Gestational age and gender of the newborn were accounted for in the multiple regression analysis. MAIN RESULTS AND THE ROLE OF CHANCE: No significant differences in mean singleton birthweight were observed between the two culture media: Medicult 3222 g (±15 SE) and Vitrolife 3251 g (±21 SE) (P = 0.264). The mean singleton birthweight was not different between Day 3 embryo transfers (3219 ± 16 g) and Day 5 blastocyst transfers (3250 ± 19 g; P = 0.209). Multiple regression analysis controlling for potential maternal, paternal, treatment and newborn confounders confirmed the non-significant differences in mean singleton birthweight between the two culture media. Likewise, the adjusted mean singleton birthweight was not different according to the duration of in vitro culture (P = 0.521). LIMITATIONS, REASONS FOR CAUTION: The conclusions are limited by its retrospective design; however, the two different sequential culture systems were used in an alternating way during the same time period. Pregnancy-associated factors possibly influencing birthweight (such as diabetes, hypertension, pre-eclampsia) were not included in the analysis. WIDER IMPLICATIONS OF THE FINDINGS: This large retrospective study does not support earlier concerns that both the type of culture medium and the duration of embryo culture influence singleton birthweight. However, a continuous surveillance of human embryo culture procedures (medium type, culture duration and other culture conditions) should remain a priority within assisted reproduction technology. STUDY FUNDING/COMPETING INTERESTS: None.

Deposition of the spermatozoon in the human oocyte at ICSI: impact on oocyte survival, fertilization and blastocyst formation.

PURPOSE: To evaluate whether the deposition of the spermatozoon in the human oocyte at ICSI has any effect on oocyte survival, fertilization, blastocyst development and quality. METHODS: In a prospective study, including 78 ICSI cycles, sibling oocytes were injected with "no intention" (group A, standard ICSI, n = 393) or "intention" to deposit the spermatozoon under the cortex (group B, n = 354). Outcome parameters were oocyte survival and fertilization, as well as blastocyst formation and quality. RESULTS: Depositing the sperm under the cortex of the oocyte was not always successful for its final position, therefore, group B was divided into three subgroups: B1 successful deposition (119 oocytes, 33.6 % of oocytes in group B); B2 initially successful but spermatozoon spontaneously relocated after 2 min (136 oocytes, 38.4 %); and B3 unsuccessful deposition (99 oocytes, 28.0 %). Group A and B were compared on an intention-to-treat basis. Additionally, A, B1, B2 and B3 were also compared. The oocyte survival and fertilization, blastocyst and top-quality blastocyst developmental rates were not significantly different. CONCLUSIONS: The procedure of depositing the spermatozoon intentionally under the oocyte cortex demanded high technical skills. Successful positioning was only obtained in 34 % of the attempts. We obtained no evidence of improved oocyte survival and fertilization, blastocyst formation and quality when the spermatozoon was permanently positioned under the oocyte cortex. Taken together, depositing the spermatozoon under the oocyte cortex is not recommended for routine ICSI application.

Live birth rates after IVF are reduced by both low and high progesterone levels on the day of human chorionic gonadotrophin administration.

STUDY QUESTION: Are low serum progesterone levels on the day of human chorionic gonadotrophin (hCG) administration detrimental for live birth delivery rates during in vitro fertilization (IVF)? SUMMARY ANSWER: Progesterone levels ≤0.5 ng/ml on the day of hCG administration hinder live birth rates. WHAT IS KNOWN ALREADY: Fundamental research has shown that the presence of late follicular phase progesterone is essential for follicular development, ovulation and endometrial receptivity. However, previous studies in patients undergoing ovarian stimulation have only assessed if progesterone levels in the higher range are detrimental for pregnancy or not. That said, information on the effect of the full range of late follicular progesterone on IVF outcomes is still lacking. STUDY DESIGN, SIZE, DURATION: This was a retrospective, single-centre cohort study with 2723 cycles performed in patients aged between 19 and 36 and undergoing controlled ovarian stimulation between January 2006 and March 2012 for their first or second attempt of IVF followed by a fresh embryo transfer (ET). PARTICIPANTS/MATERIALS, SETTING, METHODS: All patients underwent ovarian stimulation using a gonadotrophin-releasing hormone (GnRH) antagonist for pituitary down-regulation. Final oocyte maturation was triggered with hCG 36 h before oocyte retrieval. On the day of hCG administration, serum progesterone evaluation was performed. Live birth delivery rates were compared amongst various ordinal and regular progesterone intervals (≤0.50, 0.50-0.75, 0.75-1.00, 1.00-1.25, 1.25-1.50, >1.50 ng/ml) using logistic regression. MAIN RESULTS AND THE ROLE OF CHANCE: The average age of our sample was 30.5 years. Almost 82% of all embryo transfers were of a single embryo and 51.8% were performed with a Day 5 embryo. The average value (±standard deviation) of progesterone on the day of hCG administration was 1.02 ± 0.50 ng/ml and the live birth rate was 23.4%. The live birth rates (according to the above-described ordinal serum progesterone intervals) were 17.1, 25.1, 26.7, 25.5, 21.9 and 16.6%, respectively. The live birth rates were significantly lower in patients with both low (≤0.5 ng/ml) and high (>1.5 ng/ml) late follicular progesterone levels (P < 0.05). LIMITATIONS, REASONS FOR CAUTION: The main limitation of our study was its retrospective nature. Furthermore, our study was restricted to patients under GnRH antagonist pituitary suppression and requires confirmation in a GnRH agonist setting. WIDER IMPLICATIONS OF THE FINDINGS: This study comprehensively assessed the relationship between live birth delivery rates and progesterone levels on the day of hCG administration during ovarian stimulation for IVF. Clinically relevant lower (≤0.5 ng/ml) and higher (>1.5 ng/ml) progesterone level limits were determined. STUDY FUNDING/COMPETING INTERESTS: No funding was received for this study and the authors have no conflicts of interest to declare.

Impact of clomiphene citrate during ovarian stimulation on the luteal phase after GnRH agonist trigger.

The use of a gonadotrophin-releasing hormone (GnRH) agonist to trigger final oocyte maturation in a GnRH antagonist protocol has been associated with poorer clinical outcomes due to an increased luteal-phase defect. It has been shown that LH activity is crucial in a normal luteal phase. Studies assessing the LH concentrations after clomiphene citrate co-treatment have observed increased luteal-phase LH concentrations. The purpose of this prospective cohort study was to analyse the effect of clomiphene citrate on the endocrine profile in the luteal phase when using GnRH agonist trigger. This was evaluated in eight oocyte donors undergoing ovarian stimulation using clomiphene citrate in combination with recombinant FSH compared with a control group of five donors treated with recombinant FSH only. The endocrine profile was comparable in both groups, except for serum LH concentrations on the day after trigger (121.3±53.0IU/l versus 52.9±21.5IU/l, respectively, P=0.022). No significant differences in LH concentrations were found on the day of trigger or 5days after oocyte retrieval. In conclusion, a luteal-phase defect was observed despite treatment with clomiphene citrate during ovarian stimulation. The use of gonadotrophin-releasing hormone (GnRH) agonist to trigger ovulation in IVF has been associated with poorer pregnancy outcomes due to an increased luteal-phase defect. The luteal phase is the last phase of the menstrual cycle and is defined as the period between ovulation and the beginning of pregnancy or menses. It has been shown the activity of LH is crucial in a normal luteal phase. Studies assessing the LH concentrations after clomiphene citrate, an oestrogen receptor inhibitor, co-treatment have observed increased luteal-phase LH concentrations. The purpose of this prospective cohort study was to analyse the effect of clomiphene citrate on menstrual cycle day 2-6 on the hormone profile in the luteal phase when using GnRH agonist trigger. This was evaluated was in eight oocyte donors undergoing ovarian stimulation using recombinant FSH compared with a control cohort of donors treated with recombinant FSH only. The current prospective cohort study reports higher LH concentrations on the day after GnRH agonist trigger, but not 5days after oocyte retrieval (i.e. in the luteal phase). In conclusion, a luteal-phase defect was observed despite the administration of clomiphene citrate during ovarian stimulation. Additional treatment with clomiphene citrate in the follicular phase is therefore not a valid alternative to prevent luteal-phase defect after GnRH agonist trigger.

Surgical management of gastrointestinal stromal tumours: a single centre experience during the past 17 years.

BACKGROUND: Gastrointestinal stromal tumour (GIST) is a rare tumour that can arise anywhere within the gastrointestinal tract. OBJECTIVES: Our objective was to present our experience managing this rare tumour of the gastrointestinal tract. We reviewed the clinico-pathological and morphological features, our experience with surgical treatment, and the outcome GIST in our centre. PATIENTS AND METHODS: The current retrospective analysis included 64 patients with GIST observed between February 1995 and September 2012. RESULTS: There were 39 males and 25 females. The mean age was 63.2 (range 36-83). The GISTs were located in the stomach in the majority of patients (60 patients, 94.0%). The tumour was asymptomatic in 14 (21.9%) patients. The tumour size varied from 0.4 to 25 cm with a mean size of 7.9 cm. Five patients showed peritoneal or liver metastasis at diagnosis. All patients had surgery. Five patients had a R2 resection and in one patient the resection-free margin was uncertain. In our cohort we had 5 patients with metastasis at diagnosis who received adjuvant imatinib. Four patients developed metastasis in the follow-up period. Three patients died due to GIST, three other patients died due to other disease. CONCLUSIONS: Gastric GIST were more common than GIST at other locations. Surgical treatment was the main therapeutic option. Tyosine kinase receptor inhibitors was used as a first line treatment in patients with metastatic GISTs or in patients with recurrence of the disease.

What is the best cryopreservation protocol for human testicular tissue banking?

STUDY QUESTION: Is there a better alternative to the conventional cryopreservation protocols for human testicular tissue banking? SUMMARY ANSWER: Uncontrolled slow freezing (USF) using 1.5 M dimethylsulphoxide (DMSO) and 0.15 M sucrose as cryoprotectants appears to be a user-friendly and efficient method for the cryopreservation of human testicular tissue. WHAT IS KNOWN ALREADY: Currently, time-consuming controlled slow freezing (CSF) protocols that need expensive equipment are commonly used for human testicular tissue banking. USF and vitrification are cryopreservation techniques that were successfully applied in several animal models but need further exploration with human tissue. STUDY DESIGN, SIZE, DURATION: Fragments (n = 160) of testicular tissue from 14 patients undergoing vasectomy reversal were assigned to a fresh control group or one of the following cryopreservation procedures: CSF using DMSO at a concentration of 0.7 or 1.5 M in the presence (+S) or absence of sucrose (-S), USF using either 0.7 or 1.5 M DMSO combined with sucrose, solid-surface vitrification (SSV) or direct cover vitrification (DCV). MATERIALS, SETTING, METHODS: Light microscopic evaluations were performed to study apoptosis, germ cell proliferation ability, spermatogonial survival, coherence of the seminiferous epithelium and integrity of the interstitial compartment after cryopreservation. Ultrastructural alterations were studied by scoring cryodamage to four relevant testicular cell types. MAIN RESULTS AND THE ROLE OF CHANCE: The USF 1.5 M DMSO + S protocol proved not solely to prevent cell death and to preserve seminiferous epithelial coherence, interstitial compartment integrity, SG and their potential to divide but also protected the testicular cell ultrastructure. A significant reduction in the number of SG per tubule from 21.4 ± 5.6 in control tissue to 4.9 ± 2.1, 8.2 ± 5.4, 11.6 ± 5.1, 8.8 ± 3.9, 12.6 ± 4.4 and 11.7 ± 5.7 was observed after cryopreservation combined with at least one other form of cryoinjury when using CSF 0.7 M DMSO -S, CSF 0.7 M DMSO + S, CSF 1.5 M DMSO + S, USF 0.7 M DMSO + S, SSV and direct cover vitrification (DCV), respectively (P < 0.001). LIMITATIONS, REASONS FOR CAUTION: Supplementary research is required to investigate the effect on tissue functionality and to confirm this study's findings using prepubertal tissue. WIDER IMPLICATIONS OF THE FINDINGS: An optimal cryopreservation protocol enhances the chances for successful fertility restoration. USF, being an easy and cost-effective alternative to CSF, would be preferable for laboratories in developing countries or whenever tissue is to be procured from a diseased child at a site distant from the banking facility.

Influence of cell loss after vitrification or slow-freezing on further in vitro development and implantation of human Day 3 embryos.

STUDY QUESTION: Is the effect of cell loss on further cleavage and implantation different for vitrified than for slowly frozen Day 3 embryos? SUMMARY ANSWER: Vitrified embryos develop better overnight than slowly frozen embryos, regardless of the number of cells lost, but have similar implantation potential if further cleavage occurs overnight. WHAT IS KNOWN ALREADY: After slow-freezing, similar implantation rates have been obtained for intact 4-cell embryos or 4-cell embryos with 1 cell damaged. For slowly frozen Day 3 embryos, lower implantation rates have been observed when at least 25% of cells were lost. Other studies reported similar implantation potential for 7- to 8-cell embryos with 0, 1 or 2 cells damaged. No data are available on further development of vitrified embryos in relation to cell damage. STUDY DESIGN, SIZE, DURATION: Survival and overnight cleavage were retrospectively assessed for 7664 slowly frozen Day 3 embryos (study period: January 2004-December 2008) and 1827 vitrified embryos (study period: April 2010-September 2011). Overnight cleavage was assessed according to cell stage at cryopreservation and post-thaw cell loss for both protocols. The relationship between cell loss and implantation rate was analysed in a subgroup of single-embryo transfers (SETs) with 780 slowly frozen and 294 vitrified embryos. PARTICIPANTS/MATERIALS, SETTING, METHODS: Embryos with ≥6 blastomeres and ≤20% fragmentation were cryopreserved using slow controlled freezing [with dimethyl sulphoxide (DMSO) as cryoprotectant] or closed vitrification [with DMSO-ethylene glycol (EG)-sucrose (S) as cryoprotectants]. Only embryos with ≥50% of cells intact after thawing were cultured overnight and were only transferred if further cleaved. For each outcome, logistic regression analysis was performed. MAIN RESULTS AND ROLE OF CHANCE: Survival was 94 and 64% after vitrification and slow-freezing respectively. Logistic regression analysis showed that overnight cleavage of surviving embryos was higher after vitrification than after slow-freezing (P < 0.001) and decreased according to the degree of cell damage (P < 0.001). If the embryo continued to cleave after thawing, there was no effect of the number of cells lost or the cryopreservation method on its implantation potential. The implantation rates of embryos with 0, 1 or 2 cells damaged were, respectively, 21% (n = 114), 21% (n = 28) and 20% (n = 12) after slow-freezing and 20% (n = 50), 21% (n = 5) and 27% (n = 4) after vitrification. LIMITATIONS, REASONS FOR CAUTION: This analysis is retrospective and study periods for vitrification and slow-freezing are different. The number of SETs with vitrified embryos is limited. However, a large number of vitrified embryos were available to analyse the further cleavage of surviving embryos. WIDER IMPLICATIONS OF THE FINDINGS: Although it is not proved that vitrified embryos are more viable than slowly frozen embryos in terms of pregnancy outcome, vitrification yields higher survival rates, better overnight development and higher transfer rates per embryo warmed. This increases the number of frozen transfer cycles originating from a single treatment and might result in a better cumulative clinical outcome. Based on the present data, the policy to warm an extra embryo before overnight culture depends on the cell stage at cryopreservation and the cell damage after warming. For 8-cell embryos, up to two cells may be damaged compared with only one cell for 6- to 7-cell embryos, before an additional embryo is warmed. STUDY FUNDING/COMPETING INTEREST(S): none.

Reproductive potential of a metaphase II oocyte retrieved after ovarian stimulation: an analysis of 23 354 ICSI cycles.

BACKGROUND Live birth per cycle and live birth per embryo transfer are commonly used outcome measures for IVF treatment. In contrast, the assessment of the reproductive efficiency of human oocytes fertilized in vitro is seldom performed on an egg-to-egg basis. This approach may however gain importance owing to the increasingly widespread use of oocyte cryopreservation, as the technique is becoming more established. The aim of the current study is to quantify the reproductive efficiency of the oocyte according to ovarian ageing and ovarian response. METHODS We performed a retrospective analysis of the outcome of all consecutive patients attending for treatment between 1992 and 2009. The outcome in terms of live birth after fresh and cryopreserved embryo transfer per mature oocyte was calculated for 207 267 oocytes retrieved in 23 354 ovarian stimulation cycles. The oocyte utilization rate (number of live births per mature oocyte) was further analysed in relation to the ovarian response. RESULTS The oocyte utilization rate in women in the age of ≤ 37 years remains constant with a mean of 4.47% live birth per mature oocyte [95% confidence interval (CI): 4.32-4.61]. From the age of 38 years onwards, a significantly lower oocyte utilization rate was noted, declining from 3.80% at the age of 38 years to 0.78% at 43 years (P < 0.001). In this 38-43 years age group, oocyte utilization rate was no longer dependent on ovarian response (P = 0.87). CONCLUSIONS The major strength of the study, which is also its weakness, is the fact that we included a large number of cycles performed over a long period of time. According to our results, the oocyte utilization rate between 23 and 37 years of age depends largely on ovarian response and to a much lesser extent on age. From the age of 38 years onwards, the utilization rate depends largely on age and to a much lesser extent on ovarian response. Considering the increased use of oocyte freezing for fertility preservation, these data are extremely valuable as they provide an estimate of the number of oocytes needed to achieve a live birth.

Neonatal follow-up of 995 consecutively born children after embryo biopsy for PGD.

BACKGROUND: Outcome data on children born after assisted reproduction treatments are important for both patients and health-care providers. The objective of this study was to determine whether embryo biopsy as performed in PGD has an impact on the health of infants up to 2 months of age. METHODS: A prospective comparative follow-up study of children born after PGD and children born after ICSI by collecting written reports and performing a physical examination at 2 months was performed. Auxological data at birth and physical findings up to 2 months of age were compared for 995 children consecutively live born after embryo biopsy (1994-2009) and for a control group of 1507 children born after ICSI with embryo transfer on Day 5. RESULTS: No differences regarding mean term, prematurity (term <32 w and <37 w), mean birthweight, very low birthweight (<1500 g), perinatal death, major malformations and neonatal hospitalizations in singletons and multiples born following PGD versus ICSI were observed. Compared with ICSI, fewer multiples born following PGD presented a low birthweight (<2500 g) (P = 0.005). CONCLUSIONS: Embryo biopsy for PGD does not introduce extra risk to the overall medical condition of newborn children. Multiples born following embryo biopsy appear to be at lower risk for low birthweight compared with multiples born following ICSI.

Sunlight exposure and sun sensitivity associated with disability progression in multiple sclerosis.

BACKGROUND: Sunlight and vitamin D have been inversely associated with the risk of multiple sclerosis (MS). OBJECTIVE: We investigated sunlight exposure and sun sensitivity in relation to disability progression in MS. METHODS: We conducted a survey among persons with MS, registered by the Flemish MS society, Belgium, and stratified data according to relapsing-onset and progressive-onset MS. We used Kaplan-Meier survival and Cox proportional hazard regression analyses with time to Expanded Disability Status Scale (EDSS) 6 as outcome measure. Hazard ratios for the time from onset and from birth were calculated for the potentially predictive variables, adjusting for age at onset, gender and immunomodulatory treatment. RESULTS: 704 (51.3%) of the 1372 respondents had reached EDSS 6. In relapsing-onset MS, respondents reporting equal or higher levels of sun exposure than persons of the same age in the last 10 years had a decreased risk of reaching EDSS 6. In progressive-onset MS, increased sun sensitivity was associated with an increased hazard of reaching EDSS 6. CONCLUSION: The association of higher sun exposure with a better outcome in relapsing-onset MS may be explained by either a protective effect or reverse causality. Mechanisms underlying sun sensitivity might influence progression in progressive-onset MS.

Alcohol, coffee, fish, smoking and disease progression in multiple sclerosis.

BACKGROUND: Certain lifestyle factors might influence disease activity in multiple sclerosis (MS). OBJECTIVES: To investigate the consumption of alcoholic beverages, caffeinated drinks, fish and cigarette smoking in relation to disability progression in relapsing onset and progressive onset MS. METHODS: We conducted a cross-sectional survey amongst individuals with MS, registered by the Flemish MS society in Belgium. A time-to-event analysis and Cox proportional-hazard regression were performed with time to Expanded Disability Status Scale (EDSS) 6 (requiring a cane or support to walk for a distance of 100 m) as outcome measure. Hazard ratios for the time from onset and from birth were adjusted for age at onset, gender and immunomodulatory treatment. RESULTS: Data of 1372 persons with definite MS were collected. In the relapsing onset group, a decreased risk for reaching EDSS 6 was found in regular consumers of alcohol, wine, coffee and fish compared with those who never consumed these substances. Cigarette smoking was associated with an enhanced risk for reaching EDSS 6. In the progressive onset group, no association with the risk of reaching EDSS 6 was found, except for the type of fish. Preference for fatty fish was associated with an increased risk to reach EDSS 6, when lean fish was taken as the reference category. CONCLUSION: Consumption of alcoholic beverages, coffee and fish were inversely associated with progression of disability in relapsing onset MS, but not in progressive onset MS. These findings allow to support the hypothesis that different mechanisms might underlie progression of disability in relapsing and progressive onset MS.

Pre-stroke use of beta-blockers does not affect ischaemic stroke severity and outcome.

BACKGROUND AND PURPOSE: It is unclear whether pre-stroke beta-blockers use may influence stroke outcome. This study evaluates the independent effect of pre-stroke use of beta-blockers on ischaemic stroke severity and 3 months functional outcome. METHODS: Pre-stroke use of beta-blockers was investigated in 1375 ischaemic stroke patients who had been included in two placebo-controlled trials with lubeluzole. Stroke severity was assessed by either the National Institute of Health Stroke Scale (NIHSS) or the European Stroke Scale (ESS). A modified Rankin scale (mRS) score of >3 at 3 months was used as measure for the poor functional outcome. RESULTS: Two hundred and sixty four patients were on beta-blockers prior to stroke onset, and 105 patients continued treatment after their stroke. Pretreatment with beta-blockers did not influence baseline stroke severity. There was no difference in stroke severity between nonusers and those on either a selective beta(1)-blocker or a non-selective beta-blocker. The likelihood of a poor outcome at 3 months was not influenced by pre-stroke beta-blocker use or beta-blocker use before and continued after stroke onset. CONCLUSIONS: Pre-stroke use of beta-blockers does not appear to influence stroke severity and functional outcome at 3 months.

Laparoscopic resection of gastric gastrointestinal stromal tumors (GIST) is safe and effective, irrespective of tumor size.

BACKGROUND: Feasibility and long-term safety of laparoscopic removal of gastric gastrointestinal stromal tumors (GISTs) of the stomach is well established for lesions smaller than 2 cm. Our specific aim was to explore whether laparoscopic treatment is equally applicable for gastric GISTs larger than 2 cm. METHODS: Between 1997 and 2010, 31 consecutive patients presenting with a primary gastric GIST were scheduled for laparoscopic resection, irrespective of tumor size. Prerequisites for laparoscopic approach were the absence of metastases and the presence of a well-defined tumor on CT scanning without involvement of adjacent organs, the esophagogastric junction, or the pylorus of the stomach. Data were retrieved retrospectively from a prospectively collected database, including information on patient demographics, surgical procedure, complications, hospital stay, and recurrence. Diagnosis of GIST was based on microscopic analysis, including immunohistochemistry with a panel of antibodies: CD117, CD34, DOG1, S100, desmin, and smooth muscle actin. RESULTS: All 31 laparoscopic resections were carried out successfully. The most common symptoms were melena, anemia, and abdominal pain. In one case we performed a laparoscopic approach for a GIST with acute bleeding. Tumor size was smaller than 2 cm in 5 patients and larger than 2 cm in 26 patients. The median tumor size was 4.4 cm (range = 0.4-11.0 cm). Median blood loss was identical in both groups (20 ml), but duration of operation (60 vs. 103 min) and duration of hospital stay (6 vs. 8 days) were lower when tumor size was less than 2 cm. Only one patient (with tumor size <2 cm) experienced a postoperative hemorrhage. After a median follow-up of 52 months, there were no recurrences or metastases. CONCLUSION: The low morbidity rates and the long-term disease-free interval of 100% observed in our cohort indicate that laparoscopic resection is safe and effective in treating gastric GISTs, even for tumors larger than 2 cm.

Neonatal outcome of 724 children born after ICSI using non-ejaculated sperm.

BACKGROUND: Safety concerns have been expressed regarding the use of immature non-ejaculated spermatozoa for ICSI. Therefore, adverse health outcomes, birth parameters, major anomaly rates and chromosomal aberrations in children born after ICSI using testicular and epididymal sperm were investigated. METHODS: Questionnaire data and results of physical examinations of 530 children born after ICSI with testicular sperm and of 194 children born after ICSI with epididymal sperm were compared with data on 2516 ICSI children born using ejaculated sperm. RESULTS: Birth parameters, stillborn rates, prematurity rates and rates of low birthweight and very low birthweight were comparable between the non-ejaculated and the ejaculated sperm groups. The perinatal death rate was higher for twins but not for singletons in the non-ejaculated sperm group in comparison to the control cohort of children born using ejaculated sperm. A non-significant increase in major anomalies was reported in the non-ejaculated sperm group in comparison to the ejaculated sperm group. No more anomalies were observed in pre- and post-natal karyotypes from viable pregnancies established using non-ejaculated sperm versus ejaculated sperm. CONCLUSION: Overall neonatal health in terms of birth parameters, major anomalies and chromosomal aberrations in our large cohort of children born by the use of non-ejaculated sperm seems reassuring in comparison to the outcome of children born after the use of ejaculated sperm.

Association between timing of zoledronic acid infusion and hip fracture healing.

UNLABELLED: Patients in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Recurrent Fracture Trial were assessed for evidence of delayed hip fracture healing. No association was observed between zoledronic acid (ZOL) and delayed healing. We conclude that ZOL has no clinically evident effect on fracture healing, even when the drug is infused in the immediate postoperative period. INTRODUCTION: Intravenous zoledronic acid 5 mg (ZOL) given after a hip fracture reduces secondary fracture rates and mortality. It has been postulated that bisphosphonates may affect healing if given soon after a fracture. We sought to determine whether the timing of ZOL infusion affected the risk of delayed hip fracture healing. METHODS: In the HORIZON Recurrent Fracture Trial, patients were randomized within 90 days of a low-trauma hip fracture to receive either once-yearly ZOL (n = 1,065) or placebo (n = 1,062). Clinical symptoms of delayed hip fracture healing were sought at randomization, 6 months and 12 months after fracture; if present, a central adjudication committee blinded to treatment assignment reviewed radiographs and clinical records. Median follow-up was 1.9 years. RESULTS: The overall incidence of delayed healing was 3.2% (ZOL) and 2.7% (placebo; odds ratio [OR], 1.17; 95% confidence interval [CI], 0.72-1.90; p = 0.61). Logistic regression models revealed no association between ZOL and delayed healing even after adjusting for other risk factors (OR, 1.21; 95% CI, 0.74-1.99; p = 0.44). There was no interaction by timing of infusion, and nonunion rates were similar even when ZOL was given within 2 weeks of hip fracture repair. NSAID use was significantly associated with delayed fracture healing (OR, 2.55; 95% CI, 1.49-4.39; p < 0.001). CONCLUSIONS: ZOL has no clinically evident effect on fracture healing, even when the drug is infused in the immediate postoperative period.

The surgical history of the amputated limb according to the indication for revascularization: diabetic foot, acute ischaemia, aneurysmal disease, chronic arterial occlusive disease.

BACKGROUND: To investigate whether the indication for the first revascularization (diabetic foot, acute ischaemia, aneurysmal disease, chronic occlusive disease) determines the surgical history and survival time in amputated limbs. METHODS: The surgical history of lower extremities amputated between 2002 and 2009 was reviewed for the number of (endo)vascular procedures, minor amputations, wound debridements, complications requiring surgery (acute ischaemia, bleeding, graft infection) and limb survival time (LST). RESULTS: 100 limbs were included in the study. The four groups underwent a similar number of surgical procedures (mean 4.1). Diabetic foot limbs had fewer revascularizations (mean 1.3, p = 0.003) and complications (mean 0.1, p = 0.005), but more minor amputations and wound debridements (mean 1.3, p = 0.002), in a significantly shorter LST (mean 555 days, p = 0.003). Acute ischaemic limbs showed the shortest LST (mean 179 days, p = 0.003) and significantly more complications (mean 0.8, p = 0.005). Limbs initially treated for aneurysmal disease or chronic occlusive disease had the highest number of revascularizations (mean resp. 2.7 and 2.6) and the longest LST (mean resp. 1669 and 1459 days, p = 0.001). Limbs with advanced chronic occlusive disease (rest pain or gangrene) presented with fewer revascularisations (mean resp. 2.5 and 1.8, p = 0.01) and a shorter LST (mean resp. 1284 and 794 days, p = 0.004) compared to claudicants. CONCLUSIONS: Our study suggests that the surgical history and limb survival in amputated limbs is disease and stage specific, and determined by the indication of the first revascularisation.

Fast-release orodispersible tramadol as analgesia in hysterosalpingography with a metal cannula or a balloon catheter.

BACKGROUND: This study aimed to evaluate the potential benefit, in terms of pain relief, of the new oral fast-release orodispersible galvanic form of tramadol in women undergoing hysterosalpingography (HSG) with either a metal cannula or a balloon catheter. METHODS: In a randomized, double-blind, placebo-controlled, 2 x 2 factorial-design trial, conducted at a single academic centre, 128 women were assigned into groups: (I) tramadol and a metal cannula, (II) tramadol and a balloon catheter, (III) placebo and a metal cannula or (IV) placebo and a balloon catheter. The primary end-point was pain registered by the patients on 10-cm visual analogue scales (VASs) at various times during and after the procedure. Secondary end-points included side effects and pain as assessed by the same physician during HSG. RESULTS: The main effect of tramadol versus placebo medication (i.e. I and II versus III and IV) was a statistically significant difference (P < 0.001) in self-reported VAS of -0.91 (-1.35 to -0.47) on the absolute and -33% (-48% to -17%) on the relative scale in favour of tramadol. Likewise, there was a significant benefit for tramadol against placebo medication for physician-perceived VAS pain scores (39% relative reduction; P < 0.001). The main effect of the balloon catheter versus metal cannula (i.e. II and IV versus I and III) was a non-significant (P = 0.82) difference in patient-reported VAS of -0.05 (-0.49 to +0.39) and -2% (-21% to +17%). There were no medication-HSG device interactions and no differences in side effects. CONCLUSIONS: During and after HSG, fast-release orodispersible tramadol significantly reduces pain without increasing side effects.

Report on a consecutive series of 581 children born after blastomere biopsy for preimplantation genetic diagnosis.

BACKGROUND: Preimplantation genetic diagnosis (PGD) and subsequently preimplantation genetic screening (PGS) have been introduced since 1990. The difference from the already existing in vitro fertilization (IVF) technology, using intracytoplasmic sperm injection (ICSI), was the embryo biopsy at day 3 after fertilization. Although healthy children post-PGD/PGS have been born, the question of whether embryo biopsy could have any harmful effects has to be studied on large series in a prospective manner. METHODS: A prospective cohort study was undertaken from 1992 until 2005, using the same approach as for the follow-up of IVF and ICSI children conceived in the same centre. Questionnaires were sent to physicians and parents at conception and at delivery. Children were examined at 2 months of age by trained clinical geneticists whenever possible. RESULTS: Data collected on 581 post-PGD/PGS children showed that term, birthweight and major malformation rates were not statistically different from that of 2889 ICSI children, with overall rates of major malformation among these post-PGD/PGS and ICSI children being 2.13 and 3.38%, respectively (odds ratio [OR]: 0.62; exact 95% confidence limits [95% CL]: 0.31-1.15). However, the overall perinatal death rate was significantly higher among post-PGD/PGS children compared with ICSI children (4.64 versus 1.87%; OR: 2.56; 95% CL: 1.54-4.18). When stratified for multiple births, perinatal death rates among PGD/PGS singleton and ICSI singleton children were similar (1.03 versus 1.30%; OR: 0.83; 95% CL: 0.28-2.44), but significantly more perinatal deaths were seen in post-PGD/PGS multiple pregnancies compared with ICSI multiple pregnancies (11.73 versus 2.54%; OR: 5.09; 95% CL: 2.80-9.90). The overall misdiagnosis rate was below 1%. CONCLUSIONS: Embryo biopsy does not add risk factors to the health of singleton children born after PGD or PGS. The perinatal death rate in multiple pregnancies is such that both caution and long-term follow-up are required.