Gray matter volume in women with the BRCA mutation with and without ovarian removal: evidence for increased risk of late-life Alzheimer's disease or dementia.

OBJECTIVE: Ovarian removal prior to spontaneous/natural menopause (SM) is associated with increased risk of late life dementias including Alzheimer's disease. This increased risk may be related to the sudden and early loss of endogenous estradiol. Women with breast cancer gene mutations (BRCAm) are counseled to undergo oophorectomy prior to SM to significantly reduce their risk of developing breast, ovarian, and cervical cancers. There is limited evidence of the neurological effects of ovarian removal prior to the age of SM showing women without the BRCAm had cortical thinning in medial temporal lobe structures. A second study in women with BRCAm and bilateral salpingo-oophorectomy (BSO) noted changes in cognition. METHODS: The present, cross-sectional study examined whole-brain differences in gray matter (GM) volume using high-resolution, quantitative magnetic resonance imaging in women with BRCAm and intact ovaries (BRCA-preBSO [study cohort with BRCA mutation prior to oophorectomy]; n = 9) and after surgery with (BSO + estradiol-based therapy [ERT]; n = 10) and without (BSO; n = 10) postsurgical estradiol hormone therapy compared with age-matched women (age-matched controls; n = 10) with their ovaries. RESULTS: The BRCA-preBSO and BSO groups showed significantly lower GM volume in the left medial temporal and frontal lobe structures. BSO + ERT exhibited few areas of lower GM volume compared with age-matched controls. Novel to this study, we also observed that all three BRCAm groups exhibited significantly higher GM volume compared with age-matched controls, suggesting continued plasticity. CONCLUSIONS: The present study provides evidence, through lower GM volume, to support both the possibility that the BRCAm, alone, and early life BSO may play a role in increasing the risk for late-life dementia. At least for BRCAm with BSO, postsurgical ERT seems to ameliorate GM losses.

Robot-assisted pelvic and renal surgery compared with laparoscopic or open surgery: Literature review of cost-effectiveness and clinical outcomes.

BACKGROUND AND AIM: The purpose of this study was to evaluate clinical experiences and cost-effectiveness by comparing robot-assisted surgery with laparoscopic- or open surgery for pelvic and renal operations. METHODS: A narrative review was carried out. RESULTS: When using robotic-assisted surgery, oncological and functional results are similar to after laparoscopic or open surgery. One exception may be a shorter survival in cancer of the cervix uteri. In addition, postoperative complications after robotic-assisted surgery are similar, bleeding and transfusion needs are less, and the hospital stay is shorter but the preparation of the operating theater before and after surgery and the operation times are longer. Finally, robot-assisted surgery has, in several studies, been reported to be not cost-effective primarily due to high investment costs. However, more recent studies provide improved cost-effectiveness estimates due to more effective preparation of the operating theater before surgery, improved surgeon experience, and decreased investment costs. CONCLUSIONS: Complications and functional and oncological outcomes after robot-assisted surgery are similar to open surgery and laparoscopic surgery. The cost-effectiveness of robot-assisted surgery is likely to equal or surpass the alternatives.

Sex Hormones and Adrenal Steroids: Biological Variation Estimated Using Direct and Indirect Methods.

BACKGROUND: Biological variation (BV) data may be used to develop analytical performance specifications (APS), reference change values (RCV), and support the applicability of population reference intervals. This study estimates within-subject BV (CVI) for several endocrine biomarkers using 3 different methodological approaches. METHODS: For the direct method, 30 healthy volunteers were sampled weekly for 10 consecutive weeks. Samples were analyzed in duplicate for 17-hydroxyprogesterone (17-OHP), androstenedione, cortisol, cortisone, estradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), sex hormone-binding globulin (SHBG), and testosterone. A CV-ANOVA with outlier removal and a Bayesian model were applied to derive the CVI. For estradiol, FSH and LH, only the male subgroup was included. In the indirect method, using the same analytes and groups, pairs of sequential results were extracted from the laboratory information system. The total result variation for individual pairs was determined by identifying a central gaussian distribution in the ratios of the result pairs. The CVI was then estimated by removing the effect of analytical variation. RESULTS: The estimated CVI from the Bayesian model (µCVP(i)) in the total cohort was: 17-OHP, 23%; androstenedione, 20%; cortisol, 18%; cortisone, 11%; SHBG, 7.4%; testosterone, 16%; and for the sex hormones in men: estradiol, 14%; FSH, 8%; and LH, 26%. CVI-heterogeneity was present for most endocrine markers. Similar CVI data were estimated using the CV-ANOVA and the indirect method. CONCLUSIONS: Similar CVI data were obtained using 2 different direct and one indirect method. The indirect approach is a low-cost alternative ensuring implementation of CVI data applicable for local conditions.

Diagnostic accuracy for colorectal cancer of a quantitative faecal immunochemical test in symptomatic primary care patients: a study protocol.

BACKGROUND: There is increasing evidence supporting the use of faecal immunochemical tests (FIT) in patients reporting symptoms associated with colorectal cancer (CRC), but most studies until now have focused on selected subjects already referred for investigation. We therefore set out to determine the accuracy and predictive values of FIT in a primary care population. METHOD: A prospective, multicentre, single-gated comparative diagnostic study on quantitative FIT in patients aged 40 years and above presenting in primary care with symptoms associated with CRC will be conducted. Patients representing the whole spectrum of severity of such symptoms met with in primary care will be eligible and identified by GPs. Participants will answer a short form on symptoms during the last month. They will provide two faecal samples from two separate days. Analyses will be performed within 5 days (QuikRead go®, Aidian Oy). The analytical working range is 10-200 µg Hb/g faeces. Reference test will be linked to the Swedish Colorectal Cancer Registry up to 2 years after inclusion. Accuracy, area under ROC curves, and predictive values will be calculated for one FIT compared to the highest value of two FIT and at cutoff < 10, 10-14.9, 15-19.9 and ≥ 20 µg Hb/g faeces. Subgroup analyses will be conducted for patients with anaemia and those reporting rectal bleeding. A model-based cost-effectiveness analysis based on the clinical accuracy study will be performed. Based on previous literature, we hypothesized that the sensitivity of the highest value of two FIT at cutoff 10 µg Hb/g faeces will be 95% (95% CI + / - 15%). The prevalence of CRC in the study population was estimated to be 2%, and the rate of non-responders to be 1/6. In all, 3000 patients will be invited at 30 primary care centres. DISCUSSION: This study will generate important clinical real-life structured data on accuracy and predictive values of FIT in the most critical population for work-up of CRC, i.e. patients presenting with at times ambiguous symptoms in primary care. It will help establish the role of FIT in this large group. TRIAL REGISTRATION: NCT05156307 . Registered on 14 December 2021-retrospectively registered.

[Robotic-assisted pelvic and renal surgery - an overview]. / Robotassisterad bäcken- och njurkirurgi ­ en utvärdering.

Current studies indicate that robotic-assisted surgery is not inferior to laparoscopic or open surgery regarding oncologic or functional outcomes. An exception may be uterine cervix cancer, where the survival after minimal invasive surgery might not be as good as after open surgery. There is less bleeding and need for blood transfusion after robotic-assisted surgery, and postoperative complications are similar to open or laparoscopic surgery. Robotic-assisted surgery offers ergonomic advantages compared to laparoscopic surgery. The effect of the surgical learning curve is not sufficiently studied. Presently robotic-assisted surgery is not cost-effective due to high costs of investments. The operation is more time consuming than laparoscopic or open surgery with risks of delaying and cancellation of other operations.

Management of diastasis of the rectus abdominis muscles: recommendations for swedish national guidelines.

BACKGROUND: Diastasis of the rectus abdominis muscle is a common condition. There are no generally accepted criteria for diagnosis or treatment of diastasis of the rectus abdominis muscle, which causes uncertainty for the patient and healthcare providers alike. METHODS: The consensus document was created by a group of Swedish surgeons and based on a structured literature review and practical experience. RESULTS: The proposed criteria for diagnosis and treatment of diastasis of the rectus abdominis muscle are as follows: (1) Diastasis diagnosed at clinical examination using a caliper or ruler for measurement. Diagnostic imaging by ultrasound or other imaging modality, should be performed when concurrent umbilical or epigastric hernia or other cause of the patient's symptoms cannot be excluded. (2) Physiotherapy is the firsthand treatment for diastasis of the rectus abdominis muscle. Surgery should only be considered in diastasis of the rectus abdominis muscle patients with functional impairment, and not until the patient has undergone a standardized 6-month abdominal core training program. (3) The largest width of the diastasis should be at least 5 cm before surgical treatment is considered. In case of pronounced abdominal bulging or concomitant ventral hernia, surgery may be considered in patients with a smaller diastasis. (4) When surgery is undertaken, at least 2 years should have elapsed since last childbirth and future pregnancy should not be planned. (5) Plication of the linea alba is the firsthand surgical technique. Other techniques may be used but have not been found superior. DISCUSSION: The level of evidence behind these statements varies, but they are intended to lay down a standard strategy for treatment of diastasis of the rectus abdominis muscle and to enable uniformity of management.

Markers of tissue damage and inflammation after robotic and abdominal hysterectomy in early endometrial cancer: a randomised controlled trial.

The aim of this study was to analyse the dynamics of tissue damage and inflammatory response markers perioperatively and whether these differ between women operated with robotic and abdominal hysterectomy in treating early-stage endometrial cancer. At a Swedish university hospital fifty women with early-stage low-risk endometrial cancer were allocated to robotic or abdominal hysterectomy in a randomiszed controlled trial. Blood samples reflecting inflammatory responses (high sensitivity CRP, white blood cells (WBC), thrombocytes, IL-6, cortisol) and tissue damage (creatine kinase (CK), high-mobility group box 1 protein (HMGB1)) were collected one week preoperatively, just before surgery, postoperatively at two, 24 and 48 hours, and one and six weeks postoperatively. High sensitivity CRP (p = 0.03), WBC (p < 0.01), IL-6 (p = 0.03) and CK (p = 0.03) were significantly lower in the robotic group, but fast transitory. Cortisol returned to baseline two hours after robotic hysterectomy but remained elevated in the abdominal group comparable to the preoperative high levels for both groups just before surgery (p < 0.0001). Thrombocytes and HMGB1 were not affected by the mode of surgery. Postoperative inflammatory response and tissue damage were lower after robotic hysterectomy compared to abdominal hysterectomy. A significant remaining cortisol elevation two hours after surgery may reflect a higher stress response in the abdominal group.

Intraoperativ strålbehandling vid primär operation för bröstcancer - TARGIT-A-studien ej konklusiv.

The TARGIT-A (TARGeted Intraoperative radioTherapy) multicentre study of early breast cancer compared intraoperative radiotherapy with external radiotherapy. While the intraoperative radiotherapy was standardised, the external postoperative comparison treatment followed established routines in the participating treatment centres resulting in substantial variations in dosages and treatment durations. The uncertainties in the interpretation of the study results created by the design of the TARGIT-A study constitute substantial obstacles to the possible introduction of intraoperative radiotherapy for early breast cancer.

The use of error and uncertainty methods in the medical laboratory.

Error methods - compared with uncertainty methods - offer simpler, more intuitive and practical procedures for calculating measurement uncertainty and conducting quality assurance in laboratory medicine. However, uncertainty methods are preferred in other fields of science as reflected by the guide to the expression of uncertainty in measurement. When laboratory results are used for supporting medical diagnoses, the total uncertainty consists only partially of analytical variation. Biological variation, pre- and postanalytical variation all need to be included. Furthermore, all components of the measuring procedure need to be taken into account. Performance specifications for diagnostic tests should include the diagnostic uncertainty of the entire testing process. Uncertainty methods may be particularly useful for this purpose but have yet to show their strength in laboratory medicine. The purpose of this paper is to elucidate the pros and cons of error and uncertainty methods as groundwork for future consensus on their use in practical performance specifications. Error and uncertainty methods are complementary when evaluating measurement data.

Effects of high and low 17ß-estradiol doses on focal cerebral ischemia in rats.

The majority of the numerous animal studies of the effects of estrogens on cerebral ischemia have reported neuroprotective results, but a few have shown increased damage. Differences in hormone administration methods, resulting in highly different 17ß-estradiol levels, may explain the discrepancies in previously reported effects. The objective of the present study was to test the hypothesis that it is the delivered dose per se, and not the route and method of administration, that determines the effect, and that high doses are damaging while lower doses are protective. One hundred and twenty ovariectomized female Wistar rats (n = 40 per group) were randomized into three groups, subcutaneously administered different doses of 17ß-estradiol and subjected to transient middle cerebral artery occlusion. The modified sticky tape test was performed after 24 h and the rats were subsequently sacrificed for infarct size measurements. In contrast to our hypothesis, a significant negative correlation between 17ß-estradiol dose and infarct size was found (p = 0.018). Thus, no support was found for the hypothesis that 17ß-estradiol can be both neuroprotective and neurotoxic merely depending on dose. In fact, on the contrary, the findings indicate that the higher the dose of 17ß-estradiol, the smaller the infarct.

Elevated body swing test after focal cerebral ischemia in rodents: methodological considerations.

BACKGROUND: The elevated body swing test (EBST) is a behavioral test used to evaluate experimental stroke in rodents. The basic idea is that when the animal is suspended vertically by the tail, it will swing its head laterally to the left or right depending on lesion side. In a previous study from our lab using the EBST after middle cerebral artery occlusion (MCAo), rats swung contralateral to the infarct day 1 post-MCAo, but ipsilateral day 3 post-MCAo. This shift was unexpected and prompted us to perform the present study. First, the literature was systematically reviewed to elucidate whether a similar shift had been noticed before, and if consensus existed regarding swing direction. Secondly, an experiment was conducted to systematically investigate the suggested behavior. Eighty-three adult male and female Sprague-Dawley rats were subjected to MCAo or sham surgery and the EBST was performed up to 7 days after the lesion. RESULTS: Both experimentally and through systematic literature review, the present study shows that the direction of biased swing activity in the EBST for rodents after cerebral ischemia can differ and even shift over time in some situations. The EBST curve for females was significantly different from that of males after the same occlusion time (p = 0.023). CONCLUSIONS: This study highlights the importance of adequate reporting of behavioral tests for lateralization and it is concluded that the EBST cannot be recommended as a test for motor asymmetry after MCAo in rats.

Effects of high and low 17ß-estradiol doses on focal cerebral ischemia: negative results.

The reasons why some animal studies indicate that estrogens increase focal cerebral ischemic damage while others show estrogen-induced neuroprotection has hitherto not been fully elucidated. Recent evidence indicates that discrepancies in hormone administration paradigms, resulting in highly different serum hormone concentrations, may account for the dichotomy. The current study aimed to test this hypothesis. Sixty ovariectomized female rats were randomized into three groups differing in 17ß-estradiol regimens, and transient focal cerebral ischemia was subsequently induced. All animals were subjected to a small functional testing battery, and three days after MCAo they were sacrificed for infarct size assessment. Infarct sizes did not differ between groups, however clear discrepancies were seen in body weight and feeding behavior. In comparison to sham-operated animals, ovariectomized rats rapidly increased in body weight, whereas the opposite was seen in rats receiving 17beta-estradiol. The weight gain in the ovariectomized rats was paralleled by an increased food intake.

Putting polyphosphates to the test: evidence against platelet-induced activation of factor XII.

The recent claim that stimulated platelets activate the intrinsic pathway of coagulation by the release of polyphosphates has been considered a breakthrough in hemostasis research. In little more than 3 years, the original publication by Müller et al has been cited >100 times. However, none of the citing articles has sought to independently validate this potentially paradigm-shifting concept. To this end, we performed extensive experimentation in vitro and in vivo in an attempt to verify the claim that factor XII (FXII) is primarily activated by stimulated platelets. In contrast to the original assertion, platelet-derived polyphosphates were found to be weak activators of FXII, with a FXIIa-generating activity of <10% compared with equivalent concentrations of kaolin. Using different coagulation assays, it was shown that platelet contribution to whole blood coagulation was unrelated to the generation of activated FXII in vitro. Additionally, key results used to verify the hypothesis in the original study in vivo were found to be irreproducible. We conclude that platelet-derived polyphosphates are not physiologically relevant activators of FXII.

Effects of 17ß-estradiol on galanin(1-29)- and galanin(1-16)-like immunoreactivities.

There are reasons to believe that the galanin neuropeptide family could include more than the two hitherto known members (galanin(1-29) and galanin-like peptide), such as the existence of at least three galanin receptors and the fact that synthetic short-chain homologues have effects and binding sites that are distinct from those of galanin(1-29). The current study uses a radioimmunoassay based on a polyclonal rabbit antiserum raised against galanin(1-16) to study the concentrations of galanin(1-16) like immunoreactivity (LI) in the various parts of the brain and gut of ovariectomized female rats, and investigates the effects of different concentrations of estradiol on these concentrations in relation to galanin(1-29)-LI. Galanin(1-29) concentrations were increased by 17ß-estradiol administration in almost all examined tissues whereas galanin(1-16)-LI was increased by 17ß-estradiol treatment in most of the gut, but only in the pituitary of the brain. Furthermore, the relation between galanin(1-29)-LI and galanin(1-16)-LI varied substantially from tissue to tissue. The main hypothesis, that galanin(1-16)-LI would be affected by 17ß-estradiol in brain and/or gut, was confirmed in addition to the secondary hypothesis, stating that the pattern of galanin(1-16)-LI changes would differ from that of galanin(1-29). The study indicates that galanin(1-16)-LI is estrogen-responsive but that its concentrations are regulated differently from that of galanin(1-29). This is strongly indicative of a biological relevance of this potentially new member of the galanin neuropeptide family.

Ovariectomy and 17ß-estradiol replacement in rats and mice: a visual demonstration.

Estrogens are a family of female sexual hormones with an exceptionally wide spectrum of effects. When rats and mice are used in estrogen research they are commonly ovariectomized in order to ablate the rapidly cycling hormone production, replacing the 17ß-estradiol exogenously. There is, however, lack of consensus regarding how the hormone should be administered to obtain physiological serum concentrations. This is crucial since the 17ß-estradiol level/administration method profoundly influences the experimental results. We have in a series of studies characterized the different modes of 17ß-estradiol administration, finding that subcutaneous silastic capsules and per-oral nut-cream Nutella are superior to commercially available slow-release pellets (produced by the company Innovative Research of America) and daily injections in terms of producing physiological serum concentrations of 17ß-estradiol. Amongst the advantages of the nut-cream method, that previously has been used for buprenorphine administration, is that when used for estrogen administration it resembles peroral hormone replacement therapy and is non-invasive. The subcutaneous silastic capsules are convenient and produce the most stable serum concentrations. This video article contains step-by-step demonstrations of ovariectomy and 17ß-estradiol hormone replacement by silastic capsules and peroral Nutella in rats and mice, followed by a discussion of important aspects of the administration procedures.

Hot flushes in healthy aging men differ from those in men with prostate cancer and in menopausal women.

Calcitonin gene-related peptide (CGRP) seems to be involved in hot flushes in women and in castrated men. Therefore, we studied whether the plasma concentrations of CGRP changed during flushes in a group of healthy aging men. Twelve men (49-71 years) with no history of current or former prostate cancer or hormonal treatment reporting ≥ 20 flushes/week were investigated. Blood samples were drawn during and between flushes for analysis of CGRP and also androgen concentrations, that is, testosterone and bioavailable testosterone were analysed. Skin temperature and skin conductance were monitored. Thirty-five flushes were reported by 10 men. The plasma concentrations of CGRP did not increase during flushes. No significant change in skin temperature or conductance was found. CGRP is probably not involved in the mechanisms of flushes in healthy aging men. Therefore, flushes in aging healthy men seem to be different from flushes in men and women deprived of sex steroids where CGRP increases during flushes.

Methods for 17ß-oestradiol administration to rats.

Several studies indicate that the beneficial or harmful effects of oestrogens in stroke are dose-dependent. Rats are amongst the most frequently used animals in these studies, which calls for thoroughly validated methods for administering 17ß-oestradiol to rats. In an earlier study we characterised three different administration methods for 17ß-oestradiol over 42 days. The present study assesses the concentrations in a short time perspective, with the addition of a novel peroral method. Female Sprague-Dawley rats were ovariectomised and administered 17ß-oestradiol by subcutaneous injections, silastic capsules, pellets and orally (in the nut-cream Nutella(®)), respectively. One group received 17ß-oestradiol by silastic capsules without previous washout time. Blood samples were obtained after 30 minutes, 1, 2, 4, 8, 12, 24, 48 and 168 hours and serum 17ß-oestradiol (and oestrone sulphate in some samples) was subsequently analysed. For long-term characterisation, one group treated perorally was blood sampled after 2, 7, 14, 21, 28, 35 and 42 days. At sacrifice, uterine horns were weighed and subcutaneous tissue samples were taken for histological assessment. The pellets, silastic capsule and injection groups produced serum 17ß-oestradiol concentrations that were initially several orders of magnitude higher than physiological levels, while the peroral groups had 17ß-oestradiol levels that were within the physiological range during the entire experiment. The peroral method is a promising option for administering 17ß-oestradiol if physiological levels or similarity to women's oral hormone therapy are desired. Uterine weights were found to be a very crude measure of oestrogen exposure.

Mechanisms of estrogens' dose-dependent neuroprotective and neurodamaging effects in experimental models of cerebral ischemia.

Ever since the hypothesis was put forward that estrogens could protect against cerebral ischemia, numerous studies have investigated the mechanisms of their effects. Despite initial studies showing ameliorating effects, later trials in both humans and animals have yielded contrasting results regarding the fundamental issue of whether estrogens are neuroprotective or neurodamaging. Therefore, investigations of the possible mechanisms of estrogen actions in brain ischemia have been difficult to assess. A recently published systematic review from our laboratory indicates that the dichotomy in experimental rat studies may be caused by the use of insufficiently validated estrogen administration methods resulting in serum hormone concentrations far from those intended, and that physiological estrogen concentrations are neuroprotective while supraphysiological concentrations augment the damage from cerebral ischemia. This evidence offers a new perspective on the mechanisms of estrogens' actions in cerebral ischemia, and also has a direct bearing on the hormone replacement therapy debate. Estrogens affect their target organs by several different pathways and receptors, and the mechanisms proposed for their effects on stroke probably prevail in different concentration ranges. In the current article, previously suggested neuroprotective and neurodamaging mechanisms are reviewed in a hormone concentration perspective in an effort to provide a mechanistic framework for the dose-dependent paradoxical effects of estrogens in stroke. It is concluded that five protective mechanisms, namely decreased apoptosis, growth factor regulation, vascular modulation, indirect antioxidant properties and decreased inflammation, and the proposed damaging mechanism of increased inflammation, are currently supported by experiments performed in optimal biological settings.

Blood chemistry markers for evaluation of inflammatory activity in Crohn's disease during infliximab therapy.

OBJECTIVE: There is a discrepancy between clinical activity and biomarkers in inflammatory bowel disease. The Harvey-Bradshaw index (HBi) is steadfast to evaluate disease activity. A set of biological markers (high sensitive C-reactive protein [hs-CRP], calprotectin, total nitrite, soluble urokinase Plasminogen Activator Receptor [suPAR], ghrelin and endothelin) are investigated to study inflammatory activity and correlation with HBi during infliximab therapy. MATERIAL AND METHODS: Patients with Crohn's disease (n = 22) were assessed and blood samples drawn before and 1 week after infliximab infusion (5 mg/kg) and repeated after 6 months, and compared to healthy volunteers. Hs-CRP, calprotectin, suPAR, ghrelin and endothelin were analyzed with immunoassays, and total nitrite with Griess-reaction. Results were analyzed with Wilcoxon matched-pairs test, Mann-Whitney test and Spearman correlations. RESULTS: After the first infusion visit, HBi and calprotectin values decreased while nitrite increased (p < 0.05). At the 6-month visit, pre-infusion index and biomarkers had returned to baseline levels. Post-infusion, again the values of HBi, hs-CRP and calprotectin decreased (p < 0.05). The suPAR levels did not change between pre- and post-infusion periods at either visit. Calprotectin, nitrite and suPAR differed from healthy controls throughout the study (p < 0.05). Endothelin decreased with each treatment but was, like ghrelin, not different from controls. We found HBi to correlate with hs-CRP (Spearman r = 0.32, p < 0.05), but calprotectin did not, neither did nitrate nor suPAR. CONCLUSIONS: Although infliximab ameliorates Crohn's disease symptoms, inflammatory markers are not persistently normalized, indicating a chronic inflammatory condition that may require continued infliximab therapy.