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Background: Colchicine reduces risk of cardiovascular events in patients post–myocardial infarction and in patients with chronic coronary disease. It remains unclear whether this effect is related to the time of onset of treatment following an acute coronary syndrome (ACS). Objectives: This study investigates risk for major adverse cardiovascular events in relation to history and timing of prior ACS, to determine whether the benefits of colchicine are consistent independent of prior ACS status. Methods: The LoDoCo2 (Low-Dose Colchicine 2) trial randomly allocated patients with chronic coronary disease to colchicine 0.5 mg once daily or placebo. The rate of the composite of cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization was compared between patients with no prior, recent (6-24 months), remote (2-7 years), or very remote (>7 years) ACS; interaction between ACS status and colchicine treatment effect was assessed. Results: In 5,522 randomized patients, risk of the primary endpoint was independent of prior ACS status. Colchicine consistently reduced the primary endpoint in patients with no prior ACS (incidence: 2.8 vs 3.4 events per 100 person-years; hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.52-1.27), recent ACS (incidence: 2.4 vs 3.3 events per 100 person-years; HR: 0.75; 95% CI: 0.51-1.10), remote ACS (incidence: 1.8 vs 3.2 events per 100 person-years, HR: 0.55; 95% CI: 0.37-0.82), and very remote ACS (incidence: 3.0 vs 4.3 events per 100 person-years, HR: 0.70; 95% CI: 0.51-0.96) (P for interaction = 0.59). Conclusions: The benefits of colchicine are consistent irrespective of history and timing of prior ACS. (The LoDoCo2 Trial: Low Dose Colchicine for secondary prevention of cardiovascular disease [LoDoCo2] ACTRN12614000093684)

The Low-Dose Colchicine-2 (LoDoCo2) trial showed that 2-4 years exposure to colchicine 0.5 mg once daily reduced the risk of cardiovascular events in patients with chronic coronary artery disease. The potential effect of years-long exposure to colchicine on renal or liver function and creatine kinase (CK) has not been systematically evaluated and was investigated in this LoDoCo2 substudy.Blood samples drawn from 1776 participants at the close-out visit of the LoDoCo2 trial were used to measure markers of renal function (creatinine, blood urea nitrogen [BUN]), liver function (alanine aminotransferase [ALT], γ-glutamyl transferase [GGT], bilirubin and albumin), and CK. Renal and liver function as well as hyperCKemia (elevated CK) were categorized to the degree of elevation biomarkers as mild, mild/moderate, moderate/severe, and marked elevations.In total, 1776 participants (mean age 66.5 years, 72% male) contributed to this analysis, with a median exposure to trial medication of 32.7 months. Compared with placebo, colchicine was not associated with changes in creatinine and BUN but was associated with elevations in ALT (30 U/L vs. 26 U/L; p 0.01) and CK (123 U/L vs. 110 U/L; p 0.01). Most elevations in ALT and CK were mild in both treatment groups. There were no moderate to marked ALT elevations ( 5-10 × upper limit of normal [ULN]) in both treatment groups, and 6 (0.7%) colchicine-treated vs. 2 (0.2%) placebo-treated participants had moderate to marked CK elevations ( 5-10 × ULN).In chronic coronary artery disease, 2-4 years of exposure to colchicine 0.5 mg once daily was associated with small elevations in ALT and CK, but was not associated with changes in renal function.https://www.anzctr.org.au ; ACTRN12614000093684, 24 January 2014.

Contains fulltext : 286293.pdf (Publisher’s version ) (Open Access) Many popular pedagogical approaches instruct children to construct their ideas into tangible and physical products. With the prospect of implementation, do children decide to go for the most creative ideas or do they shift towards ideas that are perhaps less creative but easier to construct? We conducted a field experiment to test whether expected construction affects children's creative idea selection. In this experiment, 403 children were asked to select the most original ideas to make a toy elephant more fun to play with. We randomly assigned them to a treatment condition - in which they were informed they had to construct one of the original ideas that they selected - and a control group - in which children were informed that, after idea selection, they had to perform another task. Children who were instructed to construct the selected idea into a tangible product turned a blind eye to original ideas and preferred the more feasible ideas. Thus, pedagogical approaches that aim to stimulate creativity by instructing children to construct original ideas into tangible and physical products may unintentionally change children’s choices for creative ideas. This finding highlights the importance for educators of guiding children’s decision-making process in creative problem solving, and to be aware of children’s bias against original ideas when designing creative assignments for them. 15 p.

Background and purpose Paraneoplastic neurological syndromes with Hu‐antibodies (Hu‐PNS) are immune‐mediated disorders in patients with malignancies, most frequently small cell lung cancer, affecting both the peripheral and central nervous system (CNS). In Hu‐PNS, brainstem and cerebellar involvement are common. Here, we assessed whether eye‐movement disturbances can be used for diagnosis and monitoring of CNS involvement in Hu‐PNS. Methods Twenty‐nine patients with Hu‐PNS (17 females; mean age, 63.2 years,) and 14 healthy age‐matched controls (seven females; mean age, 60.2 years) were included. Saccadic and smooth pursuit eye movements in response to visual stimuli were recorded with video‐oculography. Eye movements were scored quantitatively (number of correction saccades, saccadic intrusions, and saccades during fixation period) and qualitatively by two eye‐movement experts. In 20 patients, up to three follow‐up measurements were made during subsequent hospital visits with fixed 4‐week intervals. Disease course was assessed using the modified Rankin Scale. Results Eye movements were disturbed in 26 of 29 Hu‐PNS patients, with horizontal eye movements being in general more impaired. Moreover, in 12 of the 14 Hu‐PNS patients without clinical CNS involvement, eye movements were disturbed. Changes in eye‐movement control over a period of up to 12 weeks were significantly correlated with the clinical response to treatment (ρ = 0.52, p = 0.02). Conclusions Hu‐PNS often affects eye‐movement control, also in the absence of CNS signs or symptoms. Eye‐movement recordings in Hu‐PNS patients might be a useful tool to objectively monitor progression and treatment efficacy in Hu‐PNS patients., Eye movements are often disturbed in patients with anti‐Hu–associated paraneoplastic neurological syndromes, including in those without clinical signs of CNS involvement. Eye‐movement recordings might contribute to determining disease progression and therapy response.

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STUDY DESIGN: A systematic overview of the literature and an agreement study.OBJECTIVES: The aim of this study is to explore the inter-professional agreement of diagnostic musculoskeletal ultrasound (DMUS) between physical therapists (PT) and radiologists, using a new classification strategy based upon the therapeutic consequences in patients with shoulder pain.BACKGROUND: DMUS is frequently used by PTs, although the agreement regarding traditional diagnostic labels between PTs and radiologists is only fair. Nevertheless, DMUS could be useful when used as a stratifying-tool.METHODS: First, a systematic overview of current evidence was performed to assess which traditional diagnostic labels could be recoded into new treatment related categories (referral to secondary care, corticosteroid injections, physical therapy, watchful waiting). Next, kappa values were calculated for these categories between PTs and radiologists.RESULTS: Only three categories were extracted, as none of the traditional diagnostic labels were classified into the 'corticosteroid injection' category. Overall, we found moderate agreement to stratify patients into treatment related categories and substantial agreement for the category 'referral to secondary care'. Both categories 'watchful waiting' and 'indication for physical therapy' showed moderate agreement between the two professions.CONCLUSION: Our results indicate that the agreement between radiologists and PTs is moderate to substantial when labelling is based on treatment consequences. DMUS might be able to help the PT to guide treatment, especially for the category 'referral to secondary care' as this showed the highest agreement. However, as this is just an explorative study, more research is needed, to validate and assess the consequences of this stratification classification for clinical care.

For women with obsessive-compulsive personality disorder (OCPD) trait symptoms, coping with childbearing and parenting could be associated with postpartum depressive symptoms. Therefore, the possible relationship between OCPD trait symptoms and trajectories of postpartum depressive symptoms was examined. A cohort of 1427 women was followed from late pregnancy until 12 months’ postpartum. Trajectories of postpartum depressive symptoms were determined using growth mixture modeling with five repeated assessments. Next, the relationship between OCPD trait symptoms and these trajectories was examined through multinomial regression. Three postpartum depressive symptom trajectories were identified: (1) low symptoms (92%), (2) increasing-decreasing symptoms (inverted u-shape) (5%), and (3) increasing symptoms (3%). OCPD trait symptoms were associated with a higher likelihood of the trajectories increasing-decreasing symptoms (OR 1.26; 95% CI 1.14–1.39) and increasing symptoms (OR 1.16; 95% CI 1.02–1.32), compared to reference trajectory (low symptoms), adjusted for age, educational level, unplanned pregnancy, previous depressive episode (s), and parity. Electronic supplementary material The online version of this article (10.1007/s00737-018-0908-0) contains supplementary material, which is available to authorized users.

Patients with erythropoietic protoporphyria (EPP), a severe painful photodermatosis, experience prodromal sensations when exposed to sunlight, which are the "warning signals" to exit the sun, as prolonged exposure causes an excruciatingly painful phototoxic attack. The unique prodromal cutaneous sensations are reversible and differ from the severe burning pain attack lasting 2-7 days. Previously, afamelanotide treatment was studied using time to pain or time outside as primary outcome measures. Since patients have an ingrained fear of sunlight, these measures did not capture the full treatment effect. We retrospectively characterized and evaluated time to prodrome (TTP) as a safer, patient-reported outcome (PRO) measure in afamelanotide-treated patients.Structured interviews recorded TTP before and during afamelanotide treatment in retrospective US and Dutch cohort studies.Thirty-one US and 58 Dutch EPP patients participated. Before afamelanotide treatment, 54.8% US and 39.7% Dutch patients reported TTP onset10 minutes in direct sunlight. In both studies, patients' TTP's were significantly longer during afamelanotide treatment (p 0.0001). All US patients' TTP increased; no TTP was10 minutes. Among Dutch patients 81% improved; only 10.3% reported TTPs 10 minutes.EPP patients reported substantial improvements in TTP during afamelanotide treatment. TTP could provide a safer, PRO-based efficacy endpoint for assessing future EPP treatments.

Preeclampsia increases the long-term risk of cardiovascular disease, possibly through occurrence of hypertension after delivery, such as masked hypertension, night-time hypertension, and an adverse systolic night-to-day blood pressure (BP) ratio. These types of hypertension are often unnoticed and can only be detected with ambulatory BP monitoring (ABPM). We aimed to determine hypertension prevalence and 24-hour BP pattern with ABPM and office BP measurements in women 1 year after severe preeclampsia. This is a retrospective cohort study. As part of a follow-up program after severe preeclampsia, 200 women underwent ABPM and an office BP measurement 1 year after delivery. We calculated hypertension prevalence (sustained hypertension, masked hypertension, and white-coat hypertension) and systolic night-to-day BP ratio (dipping pattern). Medical files and questionnaires provided information on preexisting hypertension and antihypertensive treatment. One year after delivery, 41.5% of women had hypertension (sustained hypertension, masked hypertension, or white-coat hypertension) with ABPM. Masked hypertension was most common (17.5%), followed by sustained hypertension (14.5%) and white-coat hypertension (9.5%). With sheer office BP measurement, only 24.0% of women would have been diagnosed hypertensive. Forty-six percent of women had a disadvantageous dipping pattern. Hypertension is common 1 year after experiencing severe preeclampsia. Masked hypertension and white-coat hypertension are risk factors for future cardiovascular disease and can only be diagnosed with ABPM. Therefore, ABPM should be offered to all these women at high risk of developing hypertension and possibly future cardiovascular disease.

Because stability over time is central to the definition of personality disorder, aim of the current study was to determine the stability of the Pregnancy Obsessive-Compulsive Personality Disorder (OCPD) Symptoms Checklist (N = 199 women). Strong positive correlations between assessments at 32 weeks of pregnancy and 2 and 3–3.5 years after childbirth were found (r between .62–.72), and the group mean score did not change over time. The Pregnancy OCPD Symptoms Checklist assesses stable, trait-like symptoms of OCPD.Keywords: Obsessive-compulsive personality disorder, Stability, Personality, Validation

Desmoid-type fibromatosis, also called desmoid tumor, is a locally aggressive myofibroblastic neoplasm that usually arises in deep soft tissue with significant potential for local recurrence. It displays an unpredictable clinical course. β-Catenin, the genetic key player of desmoid tumors shows nuclear accumulation due to mutations that prevent its degradation leading to activation of Wnt signaling and myofibroblastic cell proliferation. The corresponding hot spot mutations are located in exon 3 of the CTNNB1 gene or alternatively, in the APC tumor suppressor gene, most often as a germline mutation. Multifocal desmoid tumors are very rare and clinical characteristics are poorly understood. Here we present six sporadic and one familial case of multifocal desmoid tumors. Four female and three male patients, aged between 7 and 30 years (mean 18.4 years) were identified in a cohort of 1392 cases. Tumors were located in (distal) extremities, thorax, breast, abdominal wall, shoulder, and neck. Four cases showed a CTNNB1 mutation and one an APC germline mutation. In two sporadic cases no CTNNB1 mutation was identified. Four patients showed (multiple) recurrences and one patient was lost to follow-up. In conclusion, multifocal desmoid tumors are a very rare disease and may occur in sporadic cases that are characterized by recurrent CTNNB1 mutations. However, the underlying pathogenesis of multifocal desmoid tumors remains poorly understood with often aggressive clinical behavior and challenging therapeutical management.

Objective. This study explores patterns of lifestyle change and whether more threatening illness perceptions are associated with lifestyle changes post-treatment for smoking, alcohol consumption and Body Mass Index (BMI) among gynecological cancer patients.Methods. In total, 395 cancer patients (N = 221 endometrial; N = 174 ovarian) were included in this secondary analysis of longitudinal data. Lifestyle outcomes were assessed through self-reported questionnaires after initial treatment and 6, 12, and 18 months of follow-up. Illness perceptions were assessed with the Brief Illness Perception Questionnaire (BIPQ). Latent class growth curve analyses were conducted to identify patterns of lifestyle change and linear mixed models using between-subject and within-subject effects to explore the association between BIPQ items and alcohol consumption (glasses/week) and BMI (kg/m(2)).Results. After initial treatment, 15% (N = 57) of the patients smoked, 53% (N = 203) drank alcohol, and 60% (N = 236) were overweight or obese. Overall, smokers made no considerable changes, but one subgroup of low level smokers reported positive decline. A slight decrease was observed for alcohol consumption among low and moderate level alcohol drinker subgroups, whereas BMI remained stable among endometrial cancer patients and increased for ovarian cancer patients. Moreover, patients with lower trust in their treatment to cure the disease drank more alcohol (beta = 0.32 glasses/week [95% CI 0.09; 0.56]).Conclusions. Change in lifestyle after a gynecological cancer treatment is not self-evident. Moreover, more threatening illness perceptions were not related to a healthier lifestyle. This study underlines the need for lifestyle-promoting activities to facilitate lifestyle improvement among gynecological cancer patients. (C) 2017 Elsevier Inc. All rights reserved.

© 2016 Chartered Society of Physiotherapy Background Shoulder pain is one of the three main musculoskeletal complaints and more than 50% of the patients have symptoms longer than 6 months. Until now, limited data exist about the content of physiotherapy for patients with shoulder pain in primary care. Objective Describe current physiotherapeutic diagnostic- and therapeutic management, including the use of diagnostic ultrasound, in patients with shoulder pain in primary care. Design and setting A prospective cohort study in primary care physiotherapy with a 12 week follow-up. Methods Descriptive data from physiotherapists was collected, such as: the diagnostic hypotheses after patient history and physical examination, the use of specific tests and diagnostic ultrasound, the interventions used and possible changes in treatment plan. Results Subacromial impingement syndrome was the most common hypothesis after patient history (48%) as well as physical examination (39%). Diagnostic ultrasound was used in 31% and of these patients the clinical diagnosis changed in 29%. Various interventions were used in all clinical diagnoses. After 12 weeks 41% of patients still received physiotherapy treatment. Conclusions Patients with shoulder pain in physiotherapy practice frequently show signs of subacromial impingement syndrome. The interventions used by the physiotherapists were generally in line with the guideline for subacromial impingement syndrome however a small proportion of physiotherapists used massage and tape/bracing techniques. A large proportion of patients were still receiving treatment after 12 weeks when no improvement was observed. If treatment for patients with subacromial impingement shows no benefit patients should be referred back to the general practitioner or orthopedic surgeon. Conclusions from this study might be slightly biased because of the selection of physiotherapists.

BACKGROUND: Aggressive fibromatosis (AF) comprises tumors with a varying biological behavior. Genetic tumor characteristics may be predictive of recurrence; hence, the prognostic value of three specific mutations on the CTNNB1 gene was evaluated in relation to known clinicopathologic risk factors in patients with primary, sporadic AF.METHODS: In a multi-institutional retrospective cohort study of patients with primary extra-abdominal and abdominal wall AF who underwent surgical treatment, the original pathology specimens were reviewed for the presence of a T41A, S45F, and 45P mutations on the CTNNB1 gene. For these mutations, the risk of recurrence was analyzed by the Kaplan-Meier method with log-rank test. Univariable and multivariable Cox regression was performed to calculate hazard ratios.RESULTS: A total of 101 patients were analyzed. During a median follow-up of 41 months, 17 recurrences were detected; the cumulative 5-year recurrence rate was 22.8 %. A specific CTNNB1 mutation was found in 76 patients, with the majority of patients having a T41A mutation (n = 49). CTNNB1 mutations were associated with the risk of recurrence: the presence of a S45F mutation was associated with a 5-year cumulative risk of recurrence of 63.8 % (P < 0.001). Multivariable analysis showed that young age and S45F mutation were independent risk factors (P = 0.011 and P < 0.001).CONCLUSIONS: The presence of specific CTNNB1 mutations was predictive for recurrence in patients after surgical treatment for primary, sporadic extra-abdominal and abdominal AF. A S45F mutation increased the risk of recurrence significantly.

Certain women experience negative mood symptoms during the menstrual cycle and progesterone addition in estrogen treatments. In women with PMDD increased negative mood symptoms related to allopregnanolone increase during the luteal phase of ovulatory menstrual cycles. In anovulatory cycles no symptom or sex steroid increase occurs. This is unexpected as positive modulators of the GABA-A receptor are generally increasing mood. This paradoxical effect has brought forward a hypothesis that the symptoms are provoked by allopregnanolone the GABA-A receptor system. GABA-A is the major inhibitory system in the brain. Positive modulators of the GABA-A receptor include the progesterone metabolites allopregnanolone and pregnanolone, benzodiazepines, barbiturates, and alcohol. GABA-A receptor modulators are known, in low concentrations to induce adverse, anxiogenic effects whereas in higher concentrations show beneficial, calming properties. Positive GABA-A receptor modulators induce strong paradoxical effects e.g. negative mood in 3-8% of those exposed, while up to 25% have moderate symptoms thus similar as the prevalence of PMDD, 3-8% among women in fertile ages, and up to 25% have moderate symptoms of premenstrual syndrome (PMS). The mechanism behind paradoxical reaction might be similar among them who react on positive GABA-A receptor modulators and in women with PMDD. In women the severity of these mood symptoms are related to the allopregnanolone serum concentrations in an inverted U-shaped curve. Negative mood symptoms occur when the serum concentration of allopregnanolone is similar to endogenous luteal phase levels, while low and high concentrations have less effect on mood. Low to moderate progesterone/allopregnanolone concentrations in women increases the activity in the amygdala (measured with fMRI) similar to the changes seen during anxiety reactions. Higher concentrations give decreased amygdala activity similar as seen during benzodiazepine treatment with calming anxiolytic effects. Patients with PMDD show decreased sensitivity in GABA-A receptor sensitivity to diazepam and pregnanolone while increased sensitivity to allopregnanolone. This agrees with findings in animals showing a relation between changes in alpha4 and delta subunits of the GABA-A receptor and anxiogenic effects of allopregnanolone. These findings suggest that negative mood symptoms in women with PMDD are caused by the paradoxical effect of allopregnanolone mediated via the GABA-A receptor

BackgroundUp to 10–15% of women experience high levels of depressive symptoms during pregnancy. Since these levels of symptoms can vary greatly over time, the current study investigated the existence of possible longitudinal trajectories of depressive symptoms during pregnancy, and aimed to identify factors associated with these trajectories.MethodsDepressive symptoms were assessed prospectively at each trimester in 1832 women, using the Edinburgh (Postnatal) Depression Scale (E(P)DS). Growth mixture modeling was used to identify trajectories of depressive symptoms during pregnancy.ResultsThree trajectories of depressive symptoms (E(P)DS scores) were identified: low stable (class 1, reference group, 83%), decreasing (class 2, 7%), and increasing (class 3, 10%). Classes 2 and 3 had significantly higher mean E(P)DS scores (7–13 throughout pregnancy) compared to the reference group (stable; E(P)DS LimitationsDepressive symptoms were assessed by self-report rather than a diagnostic interview. The participants were more often both highly educated and of Caucasian ethnicity compared to the general Dutch population.ConclusionsPoor partner involvement was associated with increasing depressive symptoms during pregnancy. Health professionals should focus on partner involvement during pregnancy in order to identify women who are potentially vulnerable for perinatal depression.

The available data from preclinical and pharmacological studies on the role of the C-O-methyl transferase (COMT) support the hypothesis that abnormal catecholamine transmission has been implicated in the pathogenesis of mood disorders (MD). We examined the relationship of a common functional polymorphism (Val108/158Met) in the COMT gene, which accounts for four-fold variation in enzyme activity, with 'early-onset' (EO) forms (less than or equal to 25 years) of MD, including patients with major depressive disorder (EO-MDD) and bipolar patients (EO-BPD), in a European multicenter case-control sample. Our sample includes 378 MDD (120 EO-MDD), 506 BPD (222 EO-BPD) and 628 controls. An association was found between the high-activity COMT Val allele, particularly the COMT Val/Val genotype and EO-MDD. These findings suggest that the COMT Val/Val genotype may be involved in EO-MDD or may be in linkage disequilibrium with a different causative polymorphism in the vicinity. The COMT gene may have complex and pleiotropic effects on susceptibility and symptomatology of neuropsychiatric disorders.

Objective— In aortic aneurysms the arterial vessel wall is dilated because of destruction of its integrity, which may lead to lethal vessel rupture. Chronic infiltration of inflammatory cells into the vessel wall is fundamental to aneurysm pathology. We aim to limit aneurysm growth by inhibition of inflammation and reducing endothelial cell (EC) activation with immunosuppressive drug azathioprine (Aza). Approach and Results— Aza and its metabolite 6-mercaptopurine have anti-inflammatory effects on leukocytes. We here demonstrate that treatment of ECs with 6-mercaptopurine inhibits cell activation as illustrated by reduced expression of interleukin-12, CCL5, CCL2, and vascular cell adhesion molecule-1 and inhibition of monocyte–EC adhesion. The underlying mechanism of 6-mercaptopurine involves suppression of GTPase Rac1 activation, resulting in reduced phosphorylation of c-Jun-terminal-N-kinase and c-Jun. Subsequently, the effect of Aza was investigated in aneurysm formation in the angiotensin II aneurysm mouse model in apolipoprotein E–deficient mice. We demonstrated that Aza decreases de novo aortic aneurysm formation from an average aneurysm severity score of 2.1 (control group) to 0.6 (Aza group), and that Aza effectively delays aorta pathology in a progression experiment, resulting in a reduced severity score from 2.8 to 1.7 in Aza-treated mice. In line with the in vitro observations, Aza-treated mice showed less c-Jun-terminal-N-kinase activation in ECs and reduced leukocyte influx in the aortic wall. Conclusions— The immunosuppressive drug Aza has an anti-inflammatory effect and in ECs inhibits Rac1 and c-Jun-terminal-N-kinase activation, which may explain the protective effect of Aza in aneurysm development and, most importantly for clinical implications, aneurysm severity.

BACKGROUND: Shoulder pain is disabling and has a considerable socio-economic impact. Over 50% of patients presenting in primary care still have symptoms after 6 months; moreover, prognostic factors such as pain intensity, age, disability level and duration of complaints are associated with poor outcome. Most shoulder complaints in this group are categorized as non-specific. Musculoskeletal ultrasound might be a useful imaging method to detect subgroups of patients with subacromial disorders.This article describes the design of a prospective cohort study evaluating the influence of known prognostic and possible prognostic factors, such as findings from musculoskeletal ultrasound outcome and working alliance, on the recovery of shoulder pain. Also, to assess the usual physiotherapy care for shoulder pain and examine the inter-rater reliability of musculoskeletal ultrasound between radiologists and physiotherapists for patients with shoulder pain.METHODS: A prospective cohort study including an inter-rater reliability study. Patients presenting in primary care physiotherapy practice with shoulder pain are enrolled. At baseline validated questionnaires are used to measure patient characteristics, disease-specific characteristics and social factors. Physical examination is performed according to the expertise of the physiotherapists. Follow-up measurements will be performed 6, 12 and 26 weeks after inclusion. Primary outcome measure is perceived recovery, measured on a 7-point Likert scale. Logistic regression analysis will be used to evaluate the association between prognostic factors and recovery.DISCUSSION: The ShoCoDiP (Shoulder Complaints and using Diagnostic ultrasound in Physiotherapy practice) cohort study will provide information on current management of patients with shoulder pain in primary care, provide data to develop a prediction model for shoulder pain in primary care and to evaluate whether musculoskeletal ultrasound can improve prognosis.

Background Desmoid-type fibromatosis is a locally aggressive soft tissue tumour with a biological behaviour that varies between relatively indolent and progressive growth. Although there is a trend towards conservative treatment, surgery remains the standard treatment for extra-abdominal desmoid tumours. Methods Databases of three hospitals were searched to identify patients who had been treated for desmoid-type fibromatosis between November 1989 and May 2011. The risk of local recurrence was evaluated and predictive factors were assessed in patients who underwent surgical resection as initial treatment for a primary tumour. Results A total of 132 patients had surgical treatment for a primary tumour. A complete resection (R0) was achieved in 87 patients (65·9 per cent). In addition to surgery, 54 patients received radiotherapy. During a median follow-up of 38 months, 18 local recurrences were detected. The estimated 5-year cumulative risk of local recurrence was 17·6 per cent. Univariable Cox regression analysis demonstrated that the risk of local recurrence increased for extremity lesions compared with desmoids on the trunk (odds ratio 6·69, 95 per cent confidence interval 1·42 to 31·54). No significant influence of age, resection margins or adjuvant radiotherapy on the risk for local recurrence was observed. Conclusion Following surgical treatment of a primary extra-abdominal desmoid tumour, the 5-year risk of local recurrence is modest and not influenced by microscopically clear resection margins or adjuvant radiotherapy.

Mucosal immunity is considered important for protection against Clostridium difficile infection (CDI). We show that in hamsters immunized with Bacillus subtilis spores expressing a carboxy-terminal segment (TcdA 26–39 ) of C. difficile toxin A, no colonization occurs in protected animals when challenged with C. difficile strain 630. In contrast, animals immunized with toxoids showed no protection and remained fully colonized. Along with neutralizing toxins, antibodies to TcdA 26–39 (but not to toxoids), whether raised to the recombinant protein or to TcdA 26–39 expressed on the B. subtilis spore surface, cross-react with a number of seemingly unrelated proteins expressed on the vegetative cell surface or spore coat of C. difficile . These include two dehydrogenases, AdhE1 and LdhA, as well as the CdeC protein that is present on the spore. Anti-TcdA 26–39 mucosal antibodies obtained following immunization with recombinant B. subtilis spores were able to reduce the adhesion of C. difficile to mucus-producing intestinal cells. This cross-reaction is intriguing yet important since it illustrates the importance of mucosal immunity for complete protection against CDI.

Background The efficacy of the classical treatment modalities surgery and radiotherapy in the treatment of aggressive fibromatosis is presently disputed and there is a shift towards a more conservative approach. The aim of the present study is to objectify tumor growth in patients with extra-abdominal or abdominal wall aggressive fibromatosis, while adhering to a “watchful waiting” policy. Other objectives are to investigate quality of life and to identify factors associated with tumor growth, in particular the relation with the presence of a CTNNB1-gene mutation in the tumor. Design and methods GRAFITI is a nationwide, multicenter, prospective registration trial. All patients with extra-abdominal or abdominal wall aggressive fibromatosis are eligible for inclusion in the study. Main exclusion criteria are: history of familiar adenomatous polyposis, severe pain, functional impairment, life/limb threating situations in case of progressive disease. Patients included in the study will be treated with a watchful waiting policy during a period of 5 years. Imaging studies with ultrasound and magnetic resonance imaging scan will be performed during follow-up to monitor possible growth: the first years every 3 months, the second year twice and the yearly. In addition patients will be asked to complete a quality of life questionnaire on specific follow-up moments. The primary endpoint is the rate of progression per year, defined by the Response Evaluation Criteria In Solid Tumors (RECIST). Secondary endpoints are quality of life and the rate of influence on tumor progression for several factors, such as CTNNB1-mutations, age and localization. Discussion This study will provide insight in tumor behavior, the effect on quality of life and clinicopathological factors predictive of tumor progression. Trial registration The GRAFITI trial is registered in the Netherlands National Trial Register (NTR), number 4714.

Objective Paraneoplastic neurological syndromes associated with anti-Hu antibodies (Hu-PNS) are mediated by a T-cell immune response that is directed against the Hu antigens. In pregnancy, many Th1-mediated autoimmune diseases such as rheumatoid arthritis and multiple sclerosis regress. We hypothesised that this decreased disease activity during pregnancy may be related to high human chorionic gonadotropin (hCG) levels. Methods 15 Hu-PNS patients were treated in a prospective, uncontrolled and unblinded trial with 10 000 IU daily of hCG administered by intramuscular injection during 12 weeks. Primary outcome measures were functional improvement defined as a decrease of one or more points on the modified Rankin Scale (mRS) or stabilisation in patients with mRS score = 1 point. Five patients improved on the Barthel Index (33%). Conclusion Comparison with previous studies suggests that hCG may have immunomodulatory activity and may modify the course of Hu-PNS, although well-established confounding factors may have contributed in this uncontrolled trial.

Saccades are fast eye movements that direct the point of regard to a target in the visual field. Repeated post-saccadic visual errors can induce modifications of the amplitude of these saccades, a process known as saccadic adaptation. Two experiments using the same paradigm were performed to study the involvement of the cerebrum and the cerebellum in the processing of saccadic errors using functional magnetic resonance imaging and in-scanner eye movement recordings. In the first active condition, saccadic adaptation was prevented using a condition in which the saccadic target was shifted to a variable position during the saccade towards it. This condition induced random saccadic errors as opposed to the second active condition in which the saccadic target was not shifted. In the baseline condition, subjects looked at a stationary dot. Both active conditions compared with baseline evoked activation in the expected saccade-related regions using a stringent statistical threshold [the frontal and parietal eye fields, primary visual area, MT/V5, and the precuneus (V6) in the cerebrum; vermis VI-VII; and lobule VI in the cerebellum, known as the oculomotor vermis). In the direct comparison between the two active conditions, significantly more cerebellar activation (vermis VIII, lobules VIII-X, left lobule VIIb) was observed with random saccadic errors (using a more relaxed statistical threshold). These results suggest a possible role for areas outside the oculomotor vermis of the cerebellum in the processing of saccadic errors. Future studies of these areas with, e.g., electrophysiological recordings, may reveal the nature of the error signals that drive the amplitude modification of saccadic eye movements.

In this study, we examined possible differences in brain activation between smooth pursuit and optokinetic reflexive (OKR) eye movements using functional magnetic resonance imaging (fMRI). Eighteen healthy subjects performed two different eye movement paradigms. In the first paradigm, smooth pursuit eye movements were evoked by a single moving dot. In the second paradigm, optokinetic eye movements without a foveal smooth pursuit component were evoked by a moving pattern of multiple dots with a limited lifetime. As expected, the two eye movement systems show overlapping pathways, but the direct comparison of the activation patterns between the two experiments showed that the frontal eye field, MT/V5 and cerebellar area VI appear to be more activated during smooth pursuit than during optokinetic eye movements. These results showed that the smooth pursuit and optokinetic eye movement systems can be differentiated with fMRI using limited lifetime dots as an effective OKR stimulus.

Reflexive saccades are driven by visual stimulation whereas voluntary saccades require volitional control. Behavioral and lesional studies suggest that there are two separate mechanisms involved in the generation of these two types of saccades. This study investigated differences in cerebral and cerebellar activation between reflexive and self-paced voluntary saccadic eye movements using functional magnetic resonance imaging. In two experiments (whole brain and cerebellum) using the same paradigm, differences in brain activations induced by reflexive and self-paced voluntary saccades were assessed. Direct comparison of the activation patterns showed that the frontal eye fields, parietal eye field, the motion-sensitive area (MT/V5), the precuneus (V6), and the angular and the cingulate gyri were more activated in reflexive saccades than in voluntary saccades. No significant difference in activation was found in the cerebellum. Our results suggest that the alleged separate mechanisms for saccadic control of reflexive and self-paced voluntary are mainly observed in cerebral rather than cerebellar areas.

Contains fulltext : 71365.pdf (Publisher’s version ) (Closed access) The acute neural effects of progesterone are mediated by its neuroactive metabolites allopregnanolone and pregnanolone. These neurosteroids potentiate the inhibitory actions of gamma-aminobutyric acid (GABA). Progesterone is known to produce anxiolytic effects in animals, but recent animal studies suggest that pregnanolone increases anxiety after a period of low allopregnanolone concentration. This effect is potentially mediated by the amygdala and related to the negative mood symptoms in humans that are observed during increased allopregnanolone levels. Therefore, we investigated with functional magnetic resonance imaging (MRI) whether a single progesterone administration to healthy young women in their follicular phase modulates the amygdala response to salient, biologically relevant stimuli. The progesterone administration increased the plasma concentrations of progesterone and allopregnanolone to levels that are reached during the luteal phase and early pregnancy. The imaging results show that progesterone selectively increased amygdala reactivity. Furthermore, functional connectivity analyses indicate that progesterone modulated functional coupling of the amygdala with distant brain regions. These results reveal a neural mechanism by which progesterone may mediate adverse effects on anxiety and mood.

BACKGROUND AND PURPOSE: Optokinetic eye movements are elicited when tracking a moving pattern. It can be argued that a moving pattern of stripes invokes both the optokinetic and the smooth pursuit eye movement system, which may confound the observed brain activation patterns using functional magnetic resonance imaging (fMRI). A moving pattern of limited-lifetime-dot stimulation does not target the smooth pursuit eye movement system. METHODS: fMRI was used to compare the cortical activity elicited by an optokinetic eye movement response evoked by a moving pattern of stripes and a moving pattern of limited lifetime dots. RESULTS: The eye movement behavior showed that both types of stimuli evoked an adequate and similar optokinetic eye movement response, but stimulation with stripes evoked more activation in the frontal and parietal eye fields, MT/V5, and in the cerebellar area VI than stimulation with limited-lifetime dots. CONCLUSIONS: These brain areas are implicated in smooth pursuit eye movements. Our results suggest that indeed both the optokinetic and the smooth pursuit eye movement system are involved in tracking a moving pattern of stripes.

This study compares brain activation patterns evoked by smooth pursuit and by fixation suppression of the optokinetic reflex (OKR) using similar retinal stimulation. Functional magnetic resonance imaging (fMRI) was performed during smooth pursuit stimulation in which a moving target was presented on a stationary pattern of stripes, and during fixation suppression of OKR in which a stationary target was presented on a moving pattern of stripes. All subjects could effectively ignore the background pattern and were able to keep the target continuously on the fovea with few saccades, in both experiments. Smooth pursuit evoked activation in the frontal eye fields (FEF), the supplementary eye fields (SEF), the parietal eye fields (PEF), the motion-sensitive area (MT/V5), and in lobules and vermis VI of the cerebellum (oculomotor areas). Fixation suppression of OKR induced activation in the FEF, PEF, and MT/V5. The direct comparison analysis revealed more activation in the right lobule VI of the cerebellum and in the right lingual and calcarine gyri during smooth pursuit than during fixation suppression of OKR. Using similar retinal stimulation, our results show that smooth pursuit and fixation suppression of the OKR appear to activate largely overlapping pathways. The increased activity in the oculomotor areas of the cerebellum during smooth pursuit is probably due to the presence of an active eye movement component.

Cerebellar disturbances can induce a variety of motor deficits, ranging from severe ataxia to mild deficits of fine motor control. Although motor disturbances appear as an important clinical feature in many neurological disorders, mild disturbances are often difficult to assess properly. Eye movement recordings using video-oculography in a group of patients with a paraneoplastic neurological disorder revealed subtle saccadic and smooth pursuit deficits when compared to controls. We conclude that an easy quantification of eye movement control may assist in the diagnosis and follow-up of mild motor disturbances in patients with neurological disorders, especially when such signs are not overt during clinical neurological examination.

Dendritic cells (DCs) are antigen-presenting cells that play an important role in the body's immune defence against cancer. Strategies using antigen-primed DCs as tumour vaccines show promise in patients, but the approach is cumbersome to use clinically. Soluble tumour antigens can be targeted to DCs in vivo, but this often induces antigenic tolerance rather than immunity. Liposomes are vesicular lipid structures with adjuvant-like properties. Importantly, liposomes can encapsulate antigen and immunomodulatory factors, thus serving as potent delivery vehicles. Different strategies are being explored to target liposomal antigens to DCs in vivo. One approach has employed single-chain antibody fragments to the DC surface molecules CD11c and DEC-205, attached to the vesicle surface by metal-chelating linkage, to target liposomal membranes containing antigen and either interferon-gamma or lipopolysaccharide to DCs. Such membranes induce dramatic antitumour responses and immunotherapeutic effects when used as a vaccine in the murine tumour model B16-OVA melanoma. Liposomal targeting of antigen and maturation signals directly to DCs in vivo, therefore, represents a much simpler strategy for cancer immunotherapy than antigen loading DCs ex vivo.

Purpose: BCAR1, the human homologue of the rat p130Cas protein, was identified in a functional screen for human breast cancer cell proliferation resistant to antiestrogen drugs. Here, we study the prognostic value of quantitative BCAR1 levels in a large series of breast cancer specimens. Experimental Design: A specific ELISA was developed to measure BCAR1 protein levels in 2593 primary breast tumor cytosols. Tumor levels of BCAR1 were correlated with relapse-free survival (RFS) and overall survival (OS) and compared with collected data on urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor 1 (PAI-1). Results: In tumor cytosols, BCAR1 protein levels varied between 0.02 and 23 ng/mg protein. BCAR1 levels exhibited a positive correlation with steroid hormone receptor levels, age and menopausal status, and uPA and PAI-1 levels. The level of BCAR1 (continuous or categorized as low, intermediate, or high) was inversely related with RFS and OS time. Multivariate analysis showed that BCAR1 levels contributed independently to a base model containing the traditional prognostic factors for both RFS and OS (both P < 0.0001). When added together with uPA and PAI-1 in the multivariate model, BCAR1 contributed independently of PAI-1 and was favored over uPA. Interaction tests allowed for additional analyses of BCAR1 protein levels in clinically relevant subgroups stratified by nodal and menopausal status. Conclusions: The quantitative BCAR1 protein level represents a prognostic factor for RFS and OS in primary breast cancer, independent of the traditional prognostic factors and the other novel marker PAI-1.

Contains fulltext : 58623.pdf (Publisher’s version ) (Closed access) Peripheral benzodiazepine receptor (PBR) density in blood platelets and plasma allopregnanolone concentration in humans were determined following acute stress as represented by PhD examination. Fifteen healthy PhD students participated. Heart rate, blood pressure, plasma allopregnanolone, plasma cortisol, and PBR density were measured at different time points. Allopregnanolone and cortisol concentration and PBR density were significantly increased during examination. A positive correlation between allopregnanolone and PBR density was found.

Item does not contain fulltext RATIONALE: A deregulation in concentrations of the neurosteroids (allo)pregnanolone and 3alpha,5alpha-tetrahydrodeoxycorticosterone (3alpha,5alpha-TH DOC) has been found in depressed patients. These levels normalize following treatment with selective serotonin reuptake inhibitors (SSRIs). Furthermore, administration of the neurosteroid dehydroepiandrosterone (DHEA) to depressed patients is associated with an improvement in the symptoms of depression. OBJECTIVE: The aim of the present review is to clarify the mechanisms whereby neurosteroids, particularly allopregnanolone and DHEA, are involved in depression and to discuss the effect of SSRIs on allopregnanolone concentration. METHODS: Literature on preclinical and clinical research has been analyzed in relation to the pathophysiology of depression. RESULTS: Decreased plasma and cerebrospinal fluid concentrations of allopregnanolone in depressed patients increase to normal levels following effective psychopharmacological treatment. This might either be a physiological aspect of improvement in the symptoms of depression or a pharmacologically induced alteration. Several findings support the hypothesis of an antidepressant effect of allopregnanolone. These include an antidepressant effect demonstrated in an animal model of depression and a suppressing effect on corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP) gene expression. SSRIs increase levels of allopregnanolone, but this effect is not confined to this class of drugs alone. The beneficial effect of DHEA administration in depressed patients might result from its sigma 1 receptor-mediated enhancement of noradrenaline and serotonin neurotransmission, antiglucocorticoid effects, and cognition enhancing effects. CONCLUSIONS: Indirect genomic (allopregnanolone) and non-genomic (allopregnanolone and DHEA) mechanisms are involved in the neurosteroidogenic pathophysiology of depression. Clinical studies in homogeneous groups of non-pharmacologically treated depressed patients are required to elucidate this relationship further.

Item does not contain fulltext The aim of the present study was to compare the possible dependence potential of antidepressants (ADs) to benzodiazepines (BZDs). The Schedules for Clinical Assessment in Neuropsychiatry (SCAN), the Benzodiazepine Dependence Self-Report Questionnaire (Bendep-SRQ) and the Symptom Checklist-90 (SCL-90) were administered to 70 psychiatric outpatient BZD users and 54 psychiatric outpatient AD users. Significantly more Diagnostic and Statistical Manual of Mental Disorders, Third Edition Revised (DSM-III-R) as well as International Classification of Diseases, Tenth Edition (ICD-10) past year (PY) and lifetime (LT) dependence diagnoses were made in the BZD group than in the AD group. Bendep-SRQ scale scores for Problematic Use, Preoccupation and Lack of Compliance were significantly higher in the BZD group than in the AD group. The BZD group also had a higher rating on the Withdrawal scale, but this difference was not statistically significant. According to DSM-III-R and ICD-10 criteria ADs do have some dependence liability in psychiatric outpatients, but clearly to a lesser extent than BZDs. Further research is needed to differentiate the dependence potential among the various classes of ADs.

Background Aggressive fibromatoses (desmoid tumours) may be locally aggressive, but do not metastasize. Although a conservative approach is advocated for most patients, pain and functional impairment are indications for active treatment. Tumour necrosis factor (TNF) α and melphalan-based isolated limb perfusion (TM-ILP) is a limb-saving treatment modality for soft tissue tumours. This study reports the results of TM-ILP treatment in patients with aggressive fibromatosis. Methods Institutional databases of three European centres were searched. All patients who received TM-ILP treatment for aggressive fibromatosis between 1990 and 2012 were included. Before therapy, the patients were discussed at multidisciplinary tumour board meetings. Results Twenty-five patients received 28 TM-ILP treatments. The median age of patients was 28 (i.q.r. 19–34) years and median hospital stay was 8 (7–12) days. Median follow-up was 84 (34–114) months. A complete response was achieved after two TM-ILP treatments, and a partial response after 17 treatments in 16 patients. Stable disease was reported after eight treatments in seven patients, including a patient with stable disease after the first treatment and progression after the second TM-ILP. Toxicity was modest after most treatments; Wieberdink grade IV (extensive epidermolysis, and threatening or manifest compartment syndrome) was seen after two TM-ILP treatments. Systemic leakage was reported after one treatment, but did not lead to systemic toxicity. Functional outcome was good; 16 patients had no physical limitations, and six patients had some limitations but did not need medical aids. Amputation was prevented in all but three patients. Conclusion TNF-α-based ILP is effective in patients with aggressive fibromatosis.

The volume of distribution of ethanol was already established in 1930s by Widmark. However, since then the average body composition has changed considerably. The effect of the body mass index (BMI) on the volume of distribution of ethanol was evaluated in this study. Fifty healthy volunteers (23 men and 27 women), with BMI-values between 16.0 and 36.0 kg/m(2), were asked to drink a dose of 0.4 g ethanol per kilogram body weight after an overnight fast. The ethanol content was measured by a fully validated headspace-GC-FID method. The volume of distribution of ethanol varied between 0.40 and 0.68 L/kg for women, and between 0.43 and 0.73 L/kg for men. For both sexes, the volume of distribution decreased with increasing BMI. Regression analysis resulted in the following equations: volume of distribution = 0.8202 - 0.0090 x BMI for men (r = 0.66), and 0.7772 - 0.0099 x BMI for women (r = 0.78). Population probability prediction interval limits were also calculated. In view of the current study, fixed values for the volume of distribution of 0.7 L/kg and 0.6 L/kg for men and women, respectively, often applied in legal blood alcohol calculations, are mainly suited to judge underweight or normal weight people, but not obese persons. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

Scope: Due to the imminent growth of the world population, shortage of protein sources for human consumption will arise in the near future. Alternative and sustainable protein sources (e.g. insects) are being explored for the production of food and feed. In this project, the safety of Yellow mealworms (Tenebrio molitor L.) for human consumption was tested using approaches as advised by the European Food Safety Authority for allergenicity risk assessment. Methods and results: Different Yellow mealworm protein fractions were prepared, characterised, and tested for cross-reactivity using sera from patients with an inhalation or food allergy to biologically related species (House dust mite (HDM) and crustaceans) by immunoblotting and basophil activation. Furthermore, the stability was investigated using an in vitro pepsin digestion test. IgE from HDM- and crustacean allergic patients cross-reacted with Yellow mealworm proteins. This cross-reactivity was functional, as shown by the induction of basophil activation. The major cross-reactive proteins were identified as tropomyosin and arginine kinase, which are well known allergens in arthropods. These proteins were moderately stable in the pepsin stability test. Conclusion: Based on these cross-reactivity studies, there is a realistic possibility that HDM- and crustacean allergic patients may react to food containing Yellow mealworm proteins.

Background Acellular pertussis vaccines do not control pertussis. A new approach to offer protection to infants is necessary. BPZE1, a genetically modified Bordetella pertussis strain, was developed as a live attenuated nasal pertussis vaccine by genetically eliminating or detoxifying 3 toxins. Methods We performed a double-blind, placebo-controlled, dose-escalating study of BPZE1 given intranasally for the first time to human volunteers, the first trial of a live attenuated bacterial vaccine specifically designed for the respiratory tract. 12 subjects per dose group received 103, 105 or 107 colony-forming units as droplets with half of the dose in each nostril. 12 controls received the diluent. Local and systemic safety and immune responses were assessed during 6 months, and nasopharyngeal colonization with BPZE1 was determined with repeated cultures during the first 4 weeks after vaccination. Results Colonization was seen in one subject in the low dose, one in the medium dose and five in the high dose group. Significant increases in immune responses against pertussis antigens were seen in all colonized subjects. There was one serious adverse event not related to the vaccine. Other adverse events were trivial and occurred with similar frequency in the placebo and vaccine groups. Conclusions BPZE1 is safe in healthy adults and able to transiently colonize the nasopharynx. It induces immune responses in all colonized individuals. BPZE1 can thus undergo further clinical development, including dose optimization and trials in younger age groups. Trial Registration ClinicalTrials.gov NCT01188512

We have studied the production of mouse tumor necrosis factor α (mTNF) with Streptomyces lividans as host. m TNF cDNA was fused to the α-amylase-encoding gene ( aml ) of Streptomyces venezuelae ATCC15068 at 12 amino acids (aa) downstream from the signal-peptidase cleavage site so that the aa surrounding this processing site were conserved. S. lividans containing this construct secreted mTNF at moderately high levels (1–10 μg/ml) as a biologically active compound of high specific activity (1 × 10 8 units/mg protein). No unprocessed pre-protein and virtually no processed protein could be detected in the cell lysates. N-terminal aa sequence analysis indicated microheterogeneity (−3 to −6 forms) at the N-terminal site of secreted mTNF. It was demonstrated that this microheterogeneity was due to aminopeptidase activity.

The measurement of airway responsiveness in preschool children is hampered by the fact that most tests of airway caliber are difficult to carry out at a young age. Patient cooperation is only needed to a limited extent when transcutaneous oxygen tension (Ptc) is used as an indicator of airway obstruction following bronchial provocation. In 51 children, aged 6–14 years with asthma we have measured Ptc and forced expiratory volume in 1 second (FEV1) concurrently after bronchial provocation, using increasing doses of methacholine administered with a De Villbiss 646 nebulizer and a French-Rosenthal dosimeter. The shapes of the dose-response curves to Ptc and FEV1 show a close similarity. After methacholine challenge, the decrease in Ptc correlates highly with the decrease in FEV1. We conclude that in children a 20% decrease in Ptc can be used as a sensitive indicator of airway narrowing after methacholine challenge.

Contains fulltext : 52610.pdf (Publisher’s version ) (Open Access) Progesterone, or rather its neuroactive metabolite allopregnanolone, modulates amygdala activity and thereby influences anxiety. Cognition and, in particular, memory are also altered by allopregnanolone. In the present study, we investigated whether allopregnanolone modulates memory for biologically salient stimuli by influencing amygdala activity, which in turn may affect neural processes in other brain regions. A single progesterone dose was administered orally to healthy young women in a double-blind, placebo-controlled, crossover design, and participants were asked to memorize and recognize faces while undergoing functional magnetic resonance imaging. Progesterone decreased recognition accuracy without affecting reaction times. The imaging results show that the amygdala, hippocampus, and fusiform gyrus supported memory formation. Importantly, progesterone decreased responses to faces in the amygdala and fusiform gyrus during memory encoding, whereas it increased hippocampal responses. The progesterone-induced decrease in neural activity in the amygdala and fusiform gyrus predicted the decrease in memory performance across subjects. However, progesterone did not modulate the differential activation between subsequently remembered and subsequently forgotten faces in these areas. A similar pattern of results was observed in the fusiform gyrus and prefrontal cortex during memory retrieval. These results suggest that allopregnanolone impairs memory by reducing the recruitment of those brain regions that support memory formation and retrieval. Given the important role of the amygdala in the modulation of memory, these results suggest that allopregnanolone alters memory by influencing amygdala activity, which in turn may affect memory processes in other brain regions.

Contains fulltext : 52599.pdf (Publisher’s version ) (Closed access) Allopregnanolone is a known GABA(A) receptor agonist not previously given to men, or to women using oral contraceptives (OC). The effects of metabolites of sex hormones on the GABA(A) receptor are different between men and women. OC are known to change GABA(A) receptor subunit composition. These factors might play a role in the differential effect of allopregnanolone in men and women, and in women with or without OC. To study the sedative effect of and sensitivity to allopregnanolone in men and in women with OC, nine healthy men (mean age 24.6 years) and nine healthy women on OC (mean age 21.8 years) were given three, increasing, intravenous dosages (0.015, 0.03, and 0.045 mg/kg) of allopregnanolone. Saccadic eye velocity (SEV), subjective ratings, and electroencephalography (EEG) were used to evaluate the response to allopregnanolone. Repeated blood samples for analyses of serum allopregnanolone levels were drawn throughout the study day. Allopregnanolone decreased SEV more in women than in men, and increased subjective ratings of 'sedation'. The results in women on OC are similar to earlier results in women without OC. Subjective ratings of 'contentedness' decreased in men but increased in women. Serum levels of allopregnanolone were more highly increased in men compared to women. Other pharmacokinetic parameters were not different between sexes. On the EEG, beta power increased in men. In conclusion, men and women on OC reacted differently to allopregnanolone.

Background: High concentrations of breast cancer anti-estrogen resistance 1 (BCAR1) protein measured by Western blotting in primary breast tumor cytosols are associated with early disease progression and failure of tamoxifen therapy. The aim of the present study was to develop an ELISA to measure BCAR1 quantitatively in extracts of human breast cancer tissue. Methods: A recombinant fragment of BCAR1 (the human homolog of murine p130Cas) was produced in bacterial M15 cells, purified, and injected into chickens and rabbits. The generated antibodies were affinity-purified and used for the construction of an ELISA. After validation, the results obtained with the ELISA were compared with Western blot findings on primary breast tumors. Results: The detection limit the BCAR1 ELISA was 0.0031 μg/L, and the within-run imprecision (CV) was Conclusions: The ELISA measures BCAR1 in human breast cancer cytosols with high sensitivity and specificity. The assay can be used to confirm and to quantitatively extend previous semiquantitative Western blot data on the prognostic and predictive value of BCAR1 in human breast cancer; it can also be applied for other diseases.

A 22-year-old man with a known bipolar disorder was admitted to a psychiatric department for depression and suicidal ideation. He was being given isotretinoin to treat acne conglobata. During admission, he committed suicide. In the literature, isotretinoin is associated with the emergence of psychiatric symptoms. Although any casual relationship has not been identified, such a relationship cannot be ruled out. Methodologically well-performed research is lacking. However, positive dechallenge and rechallenge cases have been reported. Consequently, physicians must look out for the onset or worsening of psychiatric symptoms in patients treated with isotretinoin.

Malignant hyperthermia (MH) is a condition that manifests in susceptible individuals only on exposure to certain anaesthetic agents. Although genetically heterogeneous, mutations in the RYR1 gene (19q13.1) are associated with the majority of reported MH cases. Guidelines for the genetic diagnosis for MH susceptibility have recently been introduced by the European MH Group (EMHG). These are designed to supplement the muscle biopsy testing procedure, the in vitro contracture test (IVCT), which has been the only means of patient screening for the last 30 years and which remains the method for definitive diagnosis in suspected probands. Discordance observed in some families between IVCT phenotype and susceptibility locus genotype could limit the confidence in genetic diagnosis. We have therefore assessed the prevalence of 15 RYR1 mutations currently used in the genetic diagnosis of MH in a sample of over 500 unrelated European MH susceptible individuals and have recorded the frequency of RYR1 genotype/IVCT phenotype discordance. RYR1 mutations were detected in up to approximately 30% of families investigated. Phenotype/genotype discordance in a single individual was observed in 10 out of 196 mutation-positive families. In five families a mutation-positive/IVCT-negative individual was observed, and in the other five families a mutation-negative/IVCT-positive individual was observed. These data represent the most comprehensive assessment of RYR1 mutation prevalence and genotype/phenotype correlation analysis and highlight the possible limitations of MH screening methods. The implications for genetic diagnosis are discussed.

The interactions of cell surface receptors with their ligands, crucial for initiating many immunological responses, are often stabilized by receptor dimerization/oligomerization, and by multimeric interactions between receptors on one cell with their ligands or cognate receptors on the apposing cell. Current techniques for studying receptor-ligand interactions, however, do not always allow receptors to move laterally to enable dimerization/ oligomerization, or to interact multimerically with ligands on cell surfaces. For these reasons detection of low- affinity receptor-ligand interactions has been difficult. Utilizing a novel chelator-lipid, nitrilotriacetic acid di-tetradecylamine (NTA-DTDA), we have developed a convenient liposome system for directly detecting low-affinity receptor-ligand interactions. Our studies using recombinant soluble forms of murine CD40 and B7.1, and murine and human CD4, each possessing a hexhistidine tag, showed that these proteins can be anchored or 'engrafted' directly onto fluorescently labelled liposomes via a metal-chelating linkage with NTA-DTDA, permitting them to undergo dimerization/oligomerization and multimeric binding with ligands on cells. Fluorescence- activated cell sorter (FACS) analyses demonstrated that while there is little if any binding of soluble forms of murine CD40 and B7.1, and murine and human CD4 to cells, engrafted liposomes bind specifically to cells expressing the appropriate cognate receptor, often giving a fluorescence 4-6-fold above control cells. Such liposomes could detect directly the low-affinity interaction of murine CD40 and B7.1 with CD154- and CD28-expressing cells, respectively, and the interaction of CD4 with MHC Class II, which has hitherto defied direct detection except through mutational analysis and mAb blocking studies.