An ecological momentary assessment study of age effects on perceptive and non-perceptive clinical high-risk symptoms of psychosis.

Among individuals with clinical high risk for psychosis (CHR), perceptive symptoms are more frequent but have less clinical significance in children/adolescents compared to adults. However, findings are based on clinical interviews relying on patient's recall capacity. Ecological momentary assessment (EMA) can be used to explore experiences in real-time in the subject's daily life. The aim of this study was to assess frequency and stability of (perceptive and non-perceptive) CHR symptoms and to explore potential age effects. EMA was used in a sample of an early detection for psychosis service in Bern, Switzerland (N = 66; 11-36 years). CHR symptoms were recorded in random time intervals for seven days: eight assessments per day per subject, minimum time between prompts set at 25 min. CHR symptoms were additionally assessed with semi-structured interviews including the 'Structured Interview for Psychosis-Risk Syndromes' and the 'Schizophrenia Proneness Instruments'. Mixed-effects linear regression analysis on the frequency of CHR symptoms revealed a significant effect of age group, and the interaction CHR symptoms x age group for both perceptive and non-perceptive symptoms. Further, regarding stability of CHR symptoms, there was a significant effect of the interaction CHR symptoms x age group for perceptive symptoms only. Based on EMA, perceptive CHR symptoms were more frequently reported but less stable in children/adolescents compared with adults. Together with previous findings, our finding of higher instability/variability of perceptive symptoms in younger persons might suggest that with advancing age and more stability of CHR symptoms, clinical relevance (reduced psychosocial functioning) may increase.

Physical activity in an air-polluted environment: behavioral, psychological and neuroimaging protocol for a prospective cohort study (Healthy Aging in Industrial Environment study - Program 4).

BACKGROUND: Air pollution has been linked to increased mortality and morbidity. The Program 4 of the Healthy Aging in Industrial Environment study investigates whether the health and wellbeing benefits of physical activity (PA) can be fully realized in individuals living in highly polluted environments. Herein, we introduce the behavioral, psychological and neuroimaging protocol of the study. METHODS: This is a prospective cohort study of N = 1500 individuals aged 18-65 years comparing: (1) individuals living in the highly polluted, industrial region surrounding the city of Ostrava (n = 750), and (2) controls from the comparison region with relative low pollution levels in Southern Bohemia (n = 750). Quota sampling is used to obtain samples balanced on age, gender, PA status (60% active runners vs. 40% insufficiently active). Participants are screened and complete baseline assessments through online questionnaires and in-person lab-based assessments of physiological, biomechanical, neuroimaging and cognitive function parameters. Prospective 12-month intensive monitoring of air pollution and behavioral parameters (PA, inactivity, and sleep) follows, with a focus on PA-related injuries and psychological factors through fitness trackers, smartphones, and mobile apps. Subsequently, there will be a 5-year follow-up of the study cohort. DISCUSSION: The design of the study will allow for (1) the assessment of both short-term variation and long-term change in behavioral parameters, (2) evaluation of the incidence of musculoskeletal injuries and psychological factors impacting behavior and injury recovery, and (3) the impact that air pollution status (and change) has on behavior, psychological resilience, and injury recovery. Furthermore, the integration of MRI techniques and cognitive assessment in combination with data on behavioral, biological and environmental variables will provide an opportunity to examine brain structure and cognitive function in relation to health behavior and air pollution, as well as other factors affecting resilience against and vulnerability to adverse changes in brain structure and cognitive aging. This study will help inform individuals about personal risk factors and decision-makers about the impact of environmental factors on negative health outcomes and potential underlying biological, behavioral and psychological mechanisms. Challenges and opportunities stemming from the timing of the study that coincided with the COVID-19 pandemic are also discussed.

IgG1+ B-cell immunity predates IgE responses in epicutaneous sensitization to foods.

BACKGROUND: The generation of IgE-mediated food allergy in humans is silent and only diagnosed upon manifestation of clinical symptoms. While experimental models have been used to investigate some mechanisms of allergic sensitization, the generation of humoral immunity and memory remains to be elucidated. Here, we defined the evolution of allergen-specific B-cell responses during epicutaneous sensitization to foods. METHODS: Wild-type and genetic knockout animals, and drug or antibody strategies for cell depletion and immunoglobulin signaling blockade were used to investigate epicutaneous sensitization and disease progression; we analyzed allergen-specific germinal centers and IgG1+ memory B cells by flow cytometry, evaluated humoral responses, and determined clinical reactivity (anaphylaxis). RESULTS: Epicutaneous sensitization caused microscopic skin damage, inflammation, and recruitment of activated dendritic cells to the draining lymph nodes. This process generated allergen-specific IgG1+ germinal center B cells, serum IgG1, and anaphylaxis that was mediated by the alternative pathway. Whether we used peanut and/or ovalbumin from the egg white for sensitization, the allergen-specific IgG1+ memory compartment predominantly exhibited an immature, pro-germinal center phenotype (PDL-2- CD80- CD35+ CD73+ ). Subsequent subclinical exposures to the allergen induced IgE+ germinal center B cells, serum IgE, and likely activated the classical pathway of anaphylaxis. CONCLUSIONS: Our data demonstrate that IgG1+ B-cell immunity against food allergens in epicutaneous sensitization precedes the generation of IgE responses. Therefore, the assessment of allergen-specific cellular and humoral IgG1+ immunity may help to identify individuals at risk of developing IgE-mediated food allergy and hence provide a window for therapeutic interventions.

Affective instability across the lifespan in borderline personality disorder - a cross-sectional e-diary study.

OBJECTIVE: Longitudinal and cross-sectional studies suggest that affective instability is inversely related to greater age in borderline personality disorder (BPD). However, existing studies relied on retrospective self-reports of perceived instability. We examined affective instability in everyday life in patients with BPD and healthy controls (HCs) by age in a cross-sectional e-diary study. METHODS: Two hundred and sixty female participants between 14 and 53 years of age (130 patients with BPD and 130 HCs) carried an e-diary over 4 days. The e-diaries emitted a prompting signal in approximately hourly intervals asking participants to rate their current affective state, that is valence (ranging from pleasant to unpleasant) and tense arousal (ranging from calm/relaxed to restless/under tension). RESULTS: Multilevel analyses revealed a significant interaction of age and group predicting affective instability (valence: F(1,255.6)  = 7.59; P < 0.01; tense arousal: F(1,252)  = 6.08; P < 0.01), suggesting that affective instability significantly declines with greater age in patients with BPD. Controlling for the number of comorbid disorders and BPD severity did not change the results, illustrating an inverse relationship between age and affective instability in BPD (significant interaction of age*group for valence: F(1,238.7)  = 5.74; P < 0.02 and tense arousal: F(1,235.2)  = 5.28; P < 0.02). CONCLUSION: Affective instability during daily life declines with greater age in BPD. This decline is irrespective of comorbidity and BPD severity.

A meta-analysis on pain sensitivity in self-injury.

Individuals engaging in self-injurious behavior (SIB) frequently report absence of pain during acts of SIB. While altered pain sensitivity is discussed as a risk factor for the engagement in SIB, results have been mixed with considerable variance across reported effect sizes, in particular with respect to the effect of co-morbid psychopathology. The present meta-analysis aimed to summarize the current evidence on pain sensitivity in individuals engaging in SIB and to identify covariates of altered pain processing. Three databases were searched without restrictions. Additionally a hand search was performed and reference lists of included studies were checked for potential studies eligible for inclusion. Thirty-two studies were identified after screening 720 abstracts by two independent reviewers. Studies were included if they reported (i) an empirical investigation, in (ii) humans, including a sample of individuals engaging in (iii) SIB and a group of (iv) healthy controls, (v) receiving painful stimulation. Random-effects meta-analysis was performed on three pain-related outcomes (pain threshold, pain tolerance, pain intensity) and several population- and study-level covariates (i.e. age, sex, clinical etiology) were subjected to meta-regression. Meta-analysis revealed significant main effects associated with medium to large effect sizes for all included outcomes. Individuals engaging in SIB show greater pain threshold and tolerance and report less pain intensity compared to healthy controls. Clinical etiology and age are significant covariates of pain sensitivity in individuals engaging in SIB, such that pain threshold is further increased in borderline personality disorder compared to non-suicidal self-injury. Mechanisms underlying altered pain sensitivity are discussed.

Does the onset of bone metastasis in sunitinib-treated renal cell carcinoma patients impact the overall survival?

PURPOSE: To evaluate the impact of bone metastasis (BM) onset toward prognosis in metastatic renal cell carcinoma (mRCC) patients treated with sunitinib. METHODS: mRCC patients with BM and sunitinib as first targeted therapy between May 2005 and December 2012 were retrospectively analyzed. Patients with synchronous (s) BM or metachronous (m) BM were compared with regard to treatment and outcome [time to clinical progression (TTcP), overall survival (OS), skeletal-related events (SRE)]. Descriptive statistics, Kaplan-Meier estimation of TTcP and OS, Cox regression analyses, and a landmark analysis were administered. RESULTS: BM was identified in 127 mRCC patients; thereof, 82 sunitinib-treated patients were analyzed [sBM n = 57 (69.5 %), mBM n = 25 (30.5 %)]. Higher tumor grading (p = 0.029), male predominance (p = 0.02), and less second-line therapy (p = 0.001) were detected in sBM compared to mBM. SRE remained similar between subgroups (p = 0.462). TTcP during sunitinib was similar [median sBM 8.1 (95 % CI 3.9-12.3) vs. mBM 8.7 (95 % CI 2.7-14.8) months, p = 0.903]. OS remained significantly inferior in sBM patients compared to mBM [median sBM 21.1 (95 % CI 16-26.2) months vs. mBM 38.5 (95 % CI 15-62) months, p = 0.001], which was confirmed by landmark analyses at 1.5, 3, 6, 9, and 12 months. However, OS after occurrence of BM was similar in both groups [median sBM 24.2 (95 % CI 17.3-31.1) months vs. mBM 17.2 (95 % CI 8.4-26) months, p = 0.519]. CONCLUSIONS: mBM is associated with an improved OS compared to sBM in mRCC with sunitinib treatment, despite similar efficacy of sunitinib treatment in both groups of patients.

Conditioning pain stimulation does not affect itch induced by intra-epidermal histamine pricks but aggravates neurogenic inflammation in healthy volunteers.

This study investigated whether itch induced by intra-epidermal histamine is subjected to modulation by a standardized conditioned pain modulation (CPM) paradigm in 24 healthy volunteers. CPM was induced by computer-controlled cuff pressure algometry and histamine was introduced to the volar forearm by skin prick test punctures. Moreover, neurogenic inflammation and wheal reactions induced by histamine and autonomic nervous system responses (heart rate variability and skin conductance) were monitored. CPM did not modulate the intensity of histamine-induced itch suggesting that pruriceptive signaling is not inhibited by pain-recruited endogenous modulation, however, CPM was found to aggravate histamine-induced neurogenic inflammation, likely facilitated by efferent sympathetic fibers.

Does visualisation during urethrocystoscopy provide pain relief? Results of an observational study.

BACKGROUND: To measure the effects of real-time visualisation during urethrocystoscopy on pain in patients who underwent ambulatory urethrocystoscopy. METHODS: An observational study was designed. From June 2012 to June 2013 patients who had ambulatory urethrocystoscopy participated in the study. In order to measure pain perception we used a numeric rating scale (NRS) 0 to 10. Additional data was collected including gender, reason for intervention, use of a rigid or a flexible instrument and whether the patient had had urethrocystoscopy before. RESULTS: 185 patients were evaluated. 125 patients preferred to watch their urethrocystoscopy on a real-time video screen, 60 patients did not. There was no statistically relevant difference in pain perception between those patients who watched their urethrocystoscopy on a real-time video screen and those who did not (p = 0.063). However, men who were allowed to watch their flexible urethrocystoscopy experienced significantly less pain, than those who did not (p = 0.007). No such effects could be measured for rigid urethrocystoscopy (p = 0.317). Furthermore, women experienced significantly higher levels of pain during the urethrocystoscopy than men (p = 0.032). CONCLUSIONS: Visualisation during urethrocystoscopy procedures in general does not significantly decrease pain in patients. Nevertheless, men who undergo flexible urethrocystoscopy should be offered to watch their procedure in real-time on a video screen. To make urethrocystoscopy less painful for both genders, especially for women, should be subject to further research.

Lower heart rate variability predicts increased level of C-reactive protein 4 years later in healthy, nonsmoking adults.

BACKGROUND: Inflammation and vagally mediated heart rate variability (vmHRV) have been implicated in a number of conditions including diabetes and cardiovascular disease. Consistent with the inflammatory reflex termed the 'cholinergic anti-inflammatory pathway', numerous cross-sectional studies have demonstrated negative associations between vmHRV and inflammatory markers such as C-reactive protein (CRP). The only prospective study, however, showed the opposite: higher CRP at baseline predicted higher high-frequency heart rate variability (HF-HRV) at follow-up. Thus, additional studies are needed to examine the prospective association between vmHRV and CRP. METHODS: Healthy employees participated in a voluntary on-site health assessment. Blood samples and ambulatory heart rate recordings were obtained, and night-time HF-HRV was calculated. Useable heart rate data were available in 2007 for 106 nonsmoking employees (9% women; age 44.4 ± 8 years), all of whom returned for an identical follow-up health assessment in 2011. Bootstrapped (500 replications) bivariate (r) and partial Pearson's correlations (ppc) adjusting for sex, age and body mass index at baseline (2007) were calculated. RESULTS: Zero-order correlations indicated that higher HF-HRV was associated with lower levels of CRP at both time-points (2007: r = -0.19, P < 0.05; 2011: r = -0.34, P < 0.001). After adjustment, HF-HRV remained a significant predictor of CRP (ppc = -0.20, P < 0.05). CONCLUSION: In this study, we have provided in vivo support for the cholinergic anti-inflammatory pathway in humans. Cardiac vagal modulation at baseline predicts level of CRP 4 years later. Our findings have important implications for the role of vmHRV as a risk factor for cardiovascular disease morbidity and mortality. Interventions targeted at vmHRV might be useful in the prevention of diseases associated with elevated systemic inflammation.

Does personality dysfunction add incremental utility over general psychopathology when modeling previous suicide attempts in adolescent patients?

BACKGROUND: Identifying patients at risk for a suicide attempt (SA) is critical in adolescents with mental disorders. The current study aimed to 1) examine whether personality dysfunction (PD) is associated with previous SA, 2) explore the incremental utility of PD over psychiatric disorders in modeling previous SA. METHODS: The sample comprised of n = 498 adolescent patients (mean age = 15.41 years, 79.12 % females, inpatient 48.8 %, outpatient 51.2 %). SA in the past year, PD according to the alternative DSM-5 model for personality disorders, and psychiatric diagnoses were assessed using semi-structured interviews. Logistic regression and principal component analysis examining the associations and specific patterns of PD and SA in the past year were conducted. Hierarchical (stepwise) logistic regression was applied to investigate the incremental utility of PD over that of psychiatric diagnoses to identify individuals with SA in the past year. RESULTS: Including all facets of PD revealed a significant model with SA in the past year as outcome (χ2(12) = 106.65, McFaddens Pseudo-R2 = 0.17, p < 0.01). Adding PD to the model explained a significant amount of variance in past SA over that of psychiatric diagnoses (Pseudo-R2 = 0.18, Wald χ2 = 43.05, p < 0.01). LIMITATIONS: As we only studied past SA and due to the cross-sectional design, no conclusion regarding the prediction of future SA can be drawn. DISCUSSION: PD should routinely be assessed in adolescent patients since individuals with PD are more likely to have attempted suicide even when controlling for comorbid psychiatric disorders. PD may represent an important target for intervention in those with suicidal thoughts and behaviors.

The Global Bioequivalence Harmonisation Initiative (GBHI): Report of the fifth international EUFEPS/AAPS conference.

The series of conferences of the Global Bioequivalence Harmonisation Initiative (GBHI) was started in 2015 by the European Federation for Pharmaceutical Sciences (EUFEPS). All GBHI meetings so far were co-organised together with the American Association of Pharmaceutical Scientists (AAPS). Beginning with the 3rd workshop US-FDA joined as co-sponsor - to support global harmonisation of regulatory recommendations for bioequivalence (BE) assessment. At the 5th GBHI conference, the following BE topics were intensively discussed, and the following main conclusions were drawn: (1) Statistical considerations for BE assessment in specific situations covering scaling approaches for highly variable drug (HVD) products, two-stage adaptive design and opportunities of modelling and simulation to support BE: even though special BE study concepts like adaptive designs are not often used in practise so far, a majority of the workshop participants were in favour of a more frequent application of such approaches. The regulatory conditions relevant in this context need further concretisation and harmonisation between the regions. Moreover, modelling and simulation were considered as a promising and evolving approach, also for BE development programmes. (2) Fed versus fasting conditions in BE trials: Findings that BE between generic products could be confirmed only after fasted administration but failed under fed conditions seem more an exception than the rule. Obviously, BCS class IV compounds are most problematic in this context. Differences in critical excipients such as surfactants or pH-modifiers may be relevant reasons for different sensitivity for interactions in fasted versus fed conditions. Consequently, such deviations in composition of generic preparations should be avoided. Moreover, confirmation of BE may be generally difficult comparing different dosage forms, such like capsules versus tablets, especially in fed state. (3) BE assessment of locally acting drug products applied topically to the skin: Appropriateness and potential benefit of in-vitro tests as alternatives to clinical efficacy studies have been comprehensively discussed. In addition to the already well-established in-vitro release and permeation tests, other techniques were suggested, e.g., Raman spectroscopy or dermal open flow microperfusion. Validation of those methods is challenging and, despite significant progress already achieved during previous years, more research is needed before they may be fully accepted for regulatory purposes. (4) BE evaluation of narrow therapeutic index (NTI) drugs: The discrepancies amongst regulatory agencies in necessity of tighter BE acceptance ranges, the recommendations for inclusion of peak and total drug exposure into BE assessment with more restrictive criteria and the importance of comparison of the product-related within-subject variability for NTI drugs were debated. Arguments in favour and against the different approaches were presented and discussed but need further consideration before harmonisation can be achieved. The highly interactive meeting and extensive exchange between regulators and scientists from industry and academia resulted in useful progress in open BE issues and supported the goal of science-driven harmonisation.

The EMA assessment of encorafenib in combination with cetuximab for the treatment of adult patients with metastatic colorectal carcinoma harbouring the BRAFV600E mutation who have received prior therapy.

On 2 June 2020, a marketing authorisation valid through the European Union (EU) was issued for encorafenib in combination with cetuximab in adult patients with metastatic colorectal carcinoma (mCRC) with the BRAFV600E mutation who had received prior systemic therapy. Encorafenib plus cetuximab was evaluated in a randomised phase III trial of encorafenib plus binimetinib plus cetuximab versus encorafenib plus cetuximab versus cetuximab plus irinotecan or FOLFIRI (control arm) to adult patients with BRAFV600E mCRC who had received prior therapy for metastatic disease. The median overall survival was 9.3 months [95% confidence interval (CI): 8.05-11.30] versus 5.88 months (95% CI: 5.09-7.10) for encorafenib plus cetuximab (doublet) versus the control arm, respectively [hazard ratio (HR) 0.61, 95% CI: 0.48-0.77]. Progression-free survival (PFS) was 4.27 months (95% CI: 4.07-5.45) versus 1.54 months (95% CI: 1.48-1.91) (HR 0.44; 95% CI: 0.35-0.55). The most frequent adverse events in patients receiving encorafenib plus cetuximab were fatigue, nausea, diarrhoea, acneiform dermatitis, abdominal pain, arthralgia, decreased appetite, vomiting and rash. The aim of this manuscript is to summarise the scientific review of the application leading to regulatory approval in the EU.

Clinical outcomes after increasing bladder outlet resistance without augmentation cystoplasty in neurogenic bladder.

INTRODUCTION: Patients with neurogenic bladder (NGB) and urinary incontinence (UI) due to low bladder outlet resistance may require bladder neck procedures (BNPs) to achieve continence. These patients may also have reduced bladder capacity and or elevated detrusor storage pressures that require augmentation cystoplasty (AC). AC is not without complications that include risks for bladder rupture, urolithiasis, urinary tract infections and metabolic issues. Avoidance of AC would be helpful in patients with neurogenic urinary incontinence that have safe bladder parameters in the setting of low bladder outlet resistance. OBJECTIVE: To determine if pre-operative urodynamics could select children with NGBs and UI for isolated BNPs without AC. Additionally we sought to determine the safety of BNPs without AC and future need of AC with long-term follow-up. STUDY DESIGN: This is an IRB-approved retrospective analysis of all patients undergoing BNPs for management of neurogenic UI over a 17-year period. We separated these BNP patients into two groups: No AC + BNP (Group 1) vs. AC + BNP (Group 2). Our primary analyses focused on postoperative outcomes for patients in Group 1. Outcomes assessed included additional surgical procedures, urodynamic changes, development of CKD, new hydronephrosis (HDN) and vesicoureteral reflux (VUR). Secondary analysis included the timeline for the development of any bladder deterioration that necessitated AC in Group 1. RESULTS: 93 patients underwent BNP at a mean age of 10.8 years. Thirty did not have AC at the time of surgery (Group 1). These children had larger (p < 0.001) and more compliant (p < 0.001) bladders than Group 2 having simultaneous augmentation. At 6 years mean follow-up in Group 1 patients, three developed new reflux and three had new hydronephrosis. Nine (30%) had additional continence procedures. Twelve required (40%) AC at a mean of 23 months after the initial BNP. No patients had AC after 5 years. Detrusor end filling pressure increased 14.8 cm H2O (p = 0.028) and expected bladder capacity decreased 26.1% (p = 0.005) after isolated BNP. DISCUSSION: We found that from our cohort of patients who had normal bladder compliance and normal/near normal expected capacity preoperatively 40% required subsequent AC. We were unable to find pre-operative clinical parameters which predicted failure or conversion to AC. We found that 43.3% of our BNP without AC patients had no subsequent invasive procedures with mean 6-year follow-up. We found that none of our patients developed any degree of CKD. Finally, we found that the majority of patients that converted to AC after their BNP did so within the first 2 years after their initial BNP and no patients required augmentation 5 years post their initial BNP. This data validates that these patients require very strict follow up, particularly in the first 5 years after surgery. CONCLUSIONS: BNP without AC is safe in only a few selected patients with NGB. Despite preoperative selection, there are significant changes in bladder dynamics and 40% required subsequent augmentation. Bladder deterioration occurs early and generally in the first 2 years. Since there are no apparent reliable pre-operative variables predicting the need for subsequent AC, parents should be counseled regarding vigilant post-operative follow-up.

Synaptic vesicles have two distinct recycling pathways.

In this paper, evidence is presented that two distinct synaptic vesicle recycling pathways exist within a single terminal. One pathway emanates from the active zone, has a fast time course, involves no intermediate structures, and is blocked by exposure to high Mg2+/low Ca2+ saline, while the second pathway emanates at sites away from the active zone, has a slower time course, involves an endosomal intermediate, and is not sensitive to high Mg2+/low Ca2+. To visualize these two recycling pathways, the temperature-sensitive Drosophila mutant, shibire, in which vesicle recycling is normal at 19 degrees C but is blocked at 29 degrees C, was used. With exposure to 29 degrees C, complete vesicle depletion occurs as exocytosis proceeds while endocytosis is blocked. When the temperature is lowered to 26 degrees C, vesicle recycling membrane begins to accumulate as invaginations of the plasmalemma, but pinch-off is blocked. Under these experimental conditions, it was possible to distinguish the two separate pathways by electron microscopic analysis. These two pathways were further characterized by observing the normal recycling process at the permissive temperature, 19 degrees C. It is suggested that the function of these two recycling pathways might be to produce two distinct vesicle populations: the active zone and nonactive zone populations. The possibility that these two populations have different release characteristics and functions is discussed.

Reversible control of synaptic transmission in a single gene mutant of Drosophila melanogaster.

Synaptic transmission of the single gene mutant, shibirets1 (shi), of Drosophila melanogaster is reversibly blocked by elevated temperature. The presynaptic mechanism of transmission was studied in the neuromuscular junction of the dorsal longitudinal flight muscle of this mutant. It was observed that when the temperature was raised to 29 degrees C in shi flies, the amplitude of the excitatory junction potential (EJP) greatly diminished, the frequency of spontaneously released miniature excitatory junction potentials (MEJP's) was greatly reduced, and almost complete vesicle depletion was observed. These conditions were reversible if the temperature was lowered to 19 degrees C. These data suggest that the block in transmission is a result of vesicle depletion. It is suggested that depletion occurs not as a result of excessive release of transmitter but rather as a result of a block in the recycling of vesicles, which causes depletion as exocytosis (transmitter release) proceeds normally.

Association of rheumatoid arthritis with Mdm2 SNP309 and genetic evidence for an allele-specific interaction between MDM2 and p53 P72R variants: a case control study.

OBJECTIVE: This study examines two common, functional, single nucleotide polymorphisms (SNP) in the genes coding the human homolog of murine-double-minute-2 (MDM2) and p53 in patients with rheumatoid arthritis (RA) based on the hypothesis that p53 may be an important negative regulator of the pro-inflammatory transcription factor nuclear factor kappa b (NFKappaB). METHODS: Genomic DNA was obtained from 221 patients with RA who fulfilled at least 4 ACR criteria and from 521 healthy controls. Mdm2 SNP309 and p53 P72R were genotyped by polymerase chain reaction and restriction enzyme analysis. RESULTS: In RA patients the frequencies of the mdm2 SNP309 G allele and both G-containing genotypes were significantly reduced (G allele: OR: 0.75, 95% CI: 0.59-0.95, p=0.016; genotype TG: OR: 0.71, 95% CI: 0.50-1.00; genotype GG: OR. 0.58, 95% CI: 0.34-0.99; both: p=0.049). Concerning p53 P72R, no differences in allele or genotype frequencies were detected. A combined analysis of both polymorphisms revealed a significant interaction between them (p=0.046). In individuals carrying >1 p53 72R allele, MDM2 had a protective effect, whereas in individuals homozygous for p53 72P, MDM2 had the opposite effect. CONCLUSION: The function of MDM2 depends on the p53 P72R genotype, resulting in either an increased or reduced risk for RA. We suggest that in most cases MDM2 stabilizes the conformation of p53, whereas in p53 PP-positive subjects MDM2 supports the degradation of p53.

[Experimental and pathological changes of the neuromuscular junction]. / Remaniements expérimentaux et pathologiques de la jonction neuromusculaire.

The objective of our study was to investigate the cellular communication between the axon and its postsynaptic targets in the synapse. We used the neuromuscular junction (NMJ) model, which is a highly specialized structure between the nerve, the muscle, and the Schwann cell terminal where the motor neuron orders the muscle to contract. We used experimental models of motor nerve reimplantation in a denervated muscle to determine whether 1) the formation of new NMJ could participate in reinnervation of the muscle necessary to contraction or 2) the blockage of neurotransmitter release using botulinum toxin could be compensated by the formation of new NMJ. We also studied human genetic diseases that affect neuromuscular transmission--congenital myasthenic syndromes--to identify the mutations in the genes coding for synaptic molecules and to analyze the compensatory processes involved in NMJ dysfunction so that muscle contraction can occur in these conditions.

[Structural and molecular organization, development and maturation of the neuromuscular junction]. / Organisation structurale, moléculaire, formation et maturation de la jonction neuromusculaire.

The neuromuscular junction is made up of the apposition of highly differentiated domains of three types of cell: the motor neuronal ending, the terminal Schwann cell and the muscle postsynaptic membrane. These three components are surrounded by a basal lamina, dedicated to molecular signal exchanges controlling neuromuscular formation, maturation and maintenance. This functional and structural differentiated complex conducts synaptic neurotransmission to the skeletal muscle fiber. Nerve and muscle have distinct roles in synaptic compartment differentiation. The initial steps of this differentiation and the motor endplate formation require several postsynaptic molecular agents including agrin, the tyrosine kinase receptor MuSK. Neuregulin is essentially involved in Schwann cell survival and guidance for axonal growth.

[Pathophysiological, molecular and metabolic changes at the neuromuscular junction and the peripheral nerve after central nervous system lesions in humans]. / Caractérisation physiopathologique, moléculaire et métabolique de la jonction neuromusculaire et du nerf périphérique après lésion du système nerveux central chez l'homme.

From the elaborate information processing that takes place in the brain to the contraction of skeletal muscles, the neurotransmission pathways involve, at least in part, (1) in tissue, Na+, K+-ATPase electrogenesis making action potential (AP) propagation possible and (2) in the cell, the synthesis, maturation, and renewal of an amazing number of molecules concentrated at the neuromuscular junction (NMJ). Our aim is to clarify CNS and peripheral nerve system (PNS) interactions by determining whether the partial motor recovery sometimes observed after a lesion of the first motoneuron is related to (1) changes in active transportation of the ions in peripheral nerve and/or muscle and (2) morphological and/or molecular changes at the NMJ, illustrating a dysfunction. Peripheral nerve surgery is proposed to some spastic patients who have recovered partially after CNS lesions to improve their gait. During these surgical procedures, the nerve and muscle samples that are usually resected can be collected and analyzed. Here, we report on eight patients who showed strictly similar motor recovery 2 years after massive CNS lesions and who underwent a selective tibial neurotomy for a spastic equinus foot. In these eight spastic patients, we performed a pathophysiological, molecular, and metabolic study of their neuromuscular junctions and peripheral nerves to characterize the dysfunction of the neuromuscular transmission after a permanent CNS injury.

[Morphological study of CNS lesions and the consequences on rat neuromuscular junction and peripheral nerve using confocal laser scanning microscopy and Koelle's technique]. / Existe-t-il un retentissement sur la jonction neuromusculaire de rat lors de lésions du système nerveux central ? Etude morphologique en microscopie confocale et technique de Koelle.

STATE OF THE ART: In humans, it is currently believed that peripheral nerves remain intact after central nervous system (CNS) injuries. This should lead us to observe a lack of amyotrophy in the peripheral projection areas of CNS damage. Nevertheless, the appearance of amyotrophy, described as underuse amyotrophy, is common in victims of CNS injury. Its pathophysiology remains poorly understood and is currently being debated. Amyotrophy could result directly from the structural deterioration of a nervous fiber in the muscular area corresponding to the CNS injury caused by neuromuscular junction (NMJ) changes. AIMS OF THIS STUDY: The aims of this study were to assess the repercussions of a CNS injury on the NMJ and peripheral nerve complex and to evaluate the involvement of peripheral nerves and NMJs in plasticity. METHODOLOGY: Peripheral nerve and muscle biopsies were collected from a group of 35 female Wistar rats that had previously undergone a thoracic spinal cord hemisection (15 rats at the T2 level (group 1), 15 rats at the T6 level (group 2), and 5 matched rats used as controls). We studied the localization and expression of the NMJ molecular components in muscle specimens by immunohistochemistry using confocal microscopy. We also searched for signs of nerve and muscle degeneration using light and electron microscopy. RESULTS: We observed nonpathologic NMJs coexisting with completely denervated and partially reinnervated NMJs. We also found characteristics of embryonic behavior in rat axons secondary to axonal caliber distortions. Some authors associate this decrease in axonal activity with physiological denervation. CONCLUSION: This project was designed to improve the understanding of the mechanisms involved in the interactions between the first and second motoneurons after different types of CNS injuries, with variable functional repercussions. Our results strongly suggest that CNS injuries lead to both morphological and functional repercussions at the NMJ and the peripheral nerve.