Carbon Dioxide Reactivity Differentially Predicts Fear Expression After Extinction and Retrieval-Extinction in Rats.

Background: Cues present during a traumatic event may result in persistent fear responses. These responses can be attenuated through extinction learning, a core component of exposure therapy. Exposure/extinction is effective for some people, but not all. We recently demonstrated that carbon dioxide (CO2) reactivity predicts fear extinction memory and orexin activation and that orexin activation predicts fear extinction memory, which suggests that a CO2 challenge may enable identification of whether an individual is a good candidate for an extinction-based approach. Another method to attenuate conditioned responses, retrieval-extinction, renders the original associative memory labile via distinct neural mechanisms. The purpose of the current study was to examine whether we could replicate previous findings that retrieval-extinction is more effective than extinction at preventing the return of fear and that CO2 reactivity predicts fear memory after extinction. We also examined whether CO2 reactivity predicts fear memory after retrieval-extinction. Methods: Male rats first underwent a CO2 challenge and fear conditioning and were assigned to receive either standard extinction (n = 28) or retrieval-extinction (n = 28). Then, they underwent a long-term memory (LTM) test and a reinstatement test. Results: We found that retrieval-extinction resulted in lower freezing during extinction, LTM, and reinstatement than standard extinction. Using the best subset approach to linear regression, we found that CO2 reactivity predicted LTM after extinction and also predicted LTM after retrieval-extinction, although to a lesser degree. Conclusions: CO2 reactivity could be used as a screening tool to determine whether an individual may be a good candidate for an extinction-based therapeutic approach.

Extinction learning underlies exposure therapy, a treatment for anxiety disorders. However, not everyone benefits from exposure therapy, highlighting the need in developing approaches that may help predict which individuals will respond. We tested whether extinction or an alternative treatment called retrieval-extinction would be more effective at reducing conditioned fear responses in rats and whether the response to a carbon dioxide (CO₂) challenge would predict treatment response. We found that retrieval-extinction was more effective at reducing fear, and CO₂ reactivity was better at predicting the response to extinction. These findings could help improve treatment strategies for anxiety disorders.

States of epistemic curiosity interfere with memory for incidental scholastic facts.

Curiosity can be a powerful motivator to learn and retain new information. Evidence shows that high states of curiosity elicited by a specific source (i.e., a trivia question) can promote memory for incidental stimuli (non-target) presented close in time. The spreading effect of curiosity states on memory for other information has potential for educational applications. Specifically, it could provide techniques to improve learning for information that did not spark a sense of curiosity on its own. Here, we investigated how high states of curiosity induced through trivia questions affect memory performance for unrelated scholastic facts (e.g., scientific, English, or historical facts) presented in close temporal proximity to the trivia question. Across three task versions, participants viewed trivia questions closely followed in time by a scholastic fact unrelated to the trivia question, either just prior to or immediately following the answer to the trivia question. Participants then completed a surprise multiple-choice memory test (akin to a pop quiz) for the scholastic material. In all three task versions, memory performance was poorer for scholastic facts presented after trivia questions that had elicited high versus low levels of curiosity. These results contradict previous findings showing curiosity-enhanced memory for incidentally presented visual stimuli and suggest that target information that generates a high-curiosity state interferes with encoding complex and unrelated scholastic facts presented close in time.

Aha! and D'oh! experiences enhance learning for incidental information-new evidence supports the insight memory advantage.

Research on creative problem-solving finds that solutions achieved via spontaneous insight (i.e., Aha! moment) are better remembered than solutions reached without this sense of epiphany, referred to as an "insight memory advantage." We hypothesized that the insight memory advantage can spread to incidental information encoded in the moments surrounding insight as well. Participants (N = 291) were first given Rebus puzzles. After they indicated that they had found a solution, but before they could submit this solution, they were presented with scholastic facts that were incidental and unrelated to the problem at hand. Participants indicated whether they reached the solution via either insight or a step-by-step analysis. Memory results showed better performance for incidental scholastic facts presented when problem solving was accompanied by a spontaneous (Aha! experience) and induced (D'oh! experience) insight compared with solutions reached with analysis. This finding suggests that the memory advantage for problems solved via insight spreads to other unrelated information encoded in close temporal proximity and has implications for novel techniques to enhance learning in educational settings.

Anaphylactic Shock to Intravenous Indocyanine Green During a Robotic Right Colectomy.

Intravenous indocyanine green (IV ICG) is regarded as a safe immunofluorescence agent used to assess bowel perfusion prior to creating bowel anastomoses and aids in ureter identification during intra-abdominal surgery. We report the first instance of anaphylactic shock to IV ICG after prior toleration of ICG via an intra-ureteral route. Shortly after administering IV ICG, our patient became hypotensive and hypoxic requiring chest compressions, vasoactive medications, and thoracostomy tubes prior to identifying the symptoms as an allergic reaction. Anaphylaxis is not a recognized side effect of ICG and was not immediately considered. As ICG becomes increasingly utilized as an immunofluorescence agent among surgical specialties, increased awareness and recognition of anaphylactic shock as a potential side effect of ICG may lead to expedited diagnoses, treatment, and more critical evaluation of indications for future use. Additionally, our patient first tolerated intra-ureteral administration without a systemic reaction, suggesting a possible sensitization mechanism.

Leveraging a smartphone to perform time-gated luminescence measurements.

Empowered by advanced on-board sensors, high-performance optics packages and ever-increasing computational power, smartphones have democratized data generation, collection, and analysis. Building on this capacity, many platforms have been developed to enable its use as an optical sensing platform for colorimetric and fluorescence measurements. In this paper, we report the ability to enable a smartphone to perform laboratory quality time-resolved analysis of luminescent samples via the exploitation of the rolling shutter mechanism of the native CMOS imager. We achieve this by leveraging the smartphone's standard image capture applications, commercially available image analysis software, and housing the device within a UV-LED containing case. These low-cost modifications enable us to demonstrate the smartphone's analytical potential by performing tasks ranging from authentication and encryption to the interrogation of packaging, compounds, and physical phenomena. This approach underscores the power of repurposing existing technologies to extend the reach and inclusivity of scientific exploration, opening new avenues for data collection and analysis.

Substance Use Among Physician Assistant Students: A National Study on the Prevalence of Alcohol, Tobacco, Illicit Substances, and Medication Use.

INTRODUCTION: The purpose of this study was to discover the substance use prevalence among physician assistant students (PA-S) compared with the age-relevant general US population and to examine the frequency of stress, burnout, anxiety, and depression during the didactic and clinical phases, while accounting for the impact of the COVID-19 pandemic. METHODS: A 20-item survey instrument was created. Self-reported data included demographics, anxiety, burnout, tobacco, illicit substances, and prescription medication use. Outcome-based inventories included a modified Perceived Stress Scale, Patient Health Questionnaire-2 (PHQ-2), and Alcohol Use Disorder Identification Test-Concise. The survey was emailed to all US programs (∼270 programs; ∼25,000 students), with 54 programs approving dissemination to their students (n∼4,760). RESULTS: Of the 1432 responses (30% response rate, 96% completion rate), the final validated sample was 1378 students (56.1% didactic, 43.8% clinical). When compared with the national population, PA-S prevalence for tobacco (5.2%) and illicit substance use (9.9%) were notably lower; alcohol (53.5%) was comparable; and prescription medication (7.0%) is only reported for PA students due to the lack of a national comparison. A higher frequency of substance use was observed during the didactic (52.5%) vs clinical (47.5%) phases. Stress was the dominant factor in both phases (93.5% didactic, 86.1% clinical). Respondents reported that the COVID-19 pandemic had minimal impact on reported rates, other than alcohol. DISCUSSION: Although PA-S substance use prevalence is at or below the national population, PA programs are encouraged to review their policies and provide conversations and resources for students who may have one or more risk factors and experience a negative effect from current substance use.

Counterconditioning reduces contextual renewal in a novel context but not in the acquisition context.

As extinction is a context-dependent form of learning, conditioned responses tend to return when the conditioned stimulus (CS) is encountered outside the extinction context, known as contextual renewal. Counterconditioning is a technique that may lead to a more persistent reduction of the conditioned response. However, the effects of aversive-to-appetitive counterconditioning on contextual renewal in rodent studies are mixed. Further, research in humans is sparse, particularly direct statistical comparisons between counterconditioning and standard extinction techniques within the same study. Using a causal associative learning framework (the allergist task) implemented online, we compared the effectiveness of counterconditioning to standard extinction in preventing the renewal of judgements on the allergic properties of different food items (CSs). In a between-subjects design, 328 participants first learned that particular food items (CSs) lead to an allergic reaction in a specific restaurant (context A). Next, one CS was extinguished (no allergic reaction) while another CS was counterconditioned (positive outcome) in restaurant B. Causal judgements of the allergic properties of food items occurred in either the response acquisition context (ABA group, N = 112), the response reduction context where extinction and counterconditioning had occurred (ABB group, N = 107), or a novel context (ABC group, N = 109). Results showed that counterconditioning, compared to extinction, diminished the renewal of causal judgements to the CS in a novel context (ABC group). Still, casual judgements returned for both counter-conditioned and extinguished CSs in the response acquisition context (ABA group). Counterconditioning and extinction were similarly effective at preventing recovery of causal judgements in the response reduction context (ABB group); however, only in context B did participants choose the counter-conditioned CS as less likely to cause an allergic reaction in comparison to the extinguished CS. These findings indicate scenarios in which counterconditioning is more effective than standard extinction at diminishing the return of threat associations, with implications for improving the generalization of safety learning.

Rewarded Extinction Increases Amygdalar Connectivity and Stabilizes Long-Term Memory Traces in the vmPFC.

Neurobiological evidence in rodents indicates that threat extinction incorporates reward neurocircuitry. Consequently, incorporating reward associations with an extinction memory may be an effective strategy to persistently attenuate threat responses. Moreover, while there is considerable research on the short-term effects of extinction strategies in humans, the long-term effects of extinction are rarely considered. In a within-subjects fMRI study with both female and male participants, we compared counterconditioning (CC; a form of rewarded-extinction) to standard extinction at recent (24 h) and remote (approximately one month) retrieval tests. Relative to standard extinction, rewarded extinction diminished 24-h relapse of arousal and threat expectancy, and reduced activity in brain regions associated with the appraisal and expression of threat (e.g., thalamus, insula, periaqueductal gray). The retrieval of reward-associated extinction memory was accompanied by functional connectivity between the amygdala and the ventral striatum, whereas the retrieval of standard-extinction memories was associated with connectivity between the amygdala and ventromedial prefrontal cortex (vmPFC). One month later, the retrieval of both standard-extinction and rewarded-extinction was associated with amygdala-vmPFC connectivity. However, only rewarded extinction created a stable memory trace in the vmPFC, identified through overlapping multivariate patterns of fMRI activity from extinction to 24-h and one-month retrieval. These findings provide new evidence that reward may generate a more stable and enduring memory trace of attenuated threat in humans.SIGNIFICANCE STATEMENT Prevalent treatments for pathologic fear and anxiety are based on the principles of Pavlovian extinction. Unfortunately, extinction forms weak memories that only temporarily inhibit the retrieval of threat associations. Thus, to increase the translational relevance of extinction research, it is critical to investigate whether extinction can be augmented to form a more enduring memory, especially after long intervals. Here, we used a multiday fMRI paradigm in humans to compare the short-term and long-term neurobehavioral effects of aversive-to-appetitive counterconditioning (CC), a form of augmented extinction. Our results provide novel evidence that including an appetitive stimulus during extinction can reduce short-term threat relapse and stabilize the memory trace of extinction in the ventromedial prefrontal cortex (vmPFC), for at least one month after learning.

Predicting Reciprocal Thoracic Change, Proximal Junctional Kyphosis, and Revision Surgery in Adult Spinal Deformity.

BACKGROUND: Compensatory mechanisms in patients with adult spinal deformity (ASD) that lead to poor quality of life include positive sagittal balance and pelvic retroversion. The objective of this retrospective review was to identify demographic and radiographic parameters of sagittal alignment that are correlated with thoracic kyphosis (TK), PJK, and reoperation in patients undergoing surgical correction for ASD. METHODS: A single-center database of 155 patients with ASD undergoing surgery from 2008 to 2015 was reviewed. Patients >18 years old who underwent multilevel thoracolumbar fusion or fusion of thoracic vertebrae to the pelvis were included. Demographics and radiographic measurements of sagittal alignment were collected preoperatively, 6 weeks postoperatively, and 1 year postoperatively. Statistical analysis was performed to compare groups that did or did not develop change in thoracic kyphosis or PJK at early or late follow-up. Additionally, patients requiring reoperation were evaluated. RESULTS: Increased thoracic kyphosis was associated with older age, hypolordosis, and comorbid PJK. Early PJK was associated with older age, hypolordosis, and increased T1 pelvic angle. Reoperation was associated with older age, higher positive sagittal balance, hypolordosis, and pelvic retroversion; PJK and thoracic kyphosis did not increase risk for reoperation. CONCLUSIONS: Thoracic reciprocal change following surgical correction of ASD is highly associated with PJK, although neither increased risk of reoperation. PJK may be predicted by older age, hypolordosis, and increased T1 pelvic angle. Reoperation in patients with ASD is more likely in older patients with positive sagittal balance, a compensatory flat lower back, and compensatory pelvic retroversion.

Prediction of adolescent pelvis development using femoral head and acetabulum growth in a longitudinal radiographic study.

INTRODUCTION: Adolescent total hip arthroplasty (THA) is guarded partially due unclarity as to when pediatric hip joints reach full development. This study sought to identify when maximum acetabular and femoral head diameters are achieved with relation to chronological and skeletal age. MATERIALS AND METHODS: Consecutive femoral head and acetabular diameters were measured in a random sample of 54 female and 78 male subjects, which were queried from a historical collection of annual radiographs of children. Femoral head and triradiate physeal plates were scored according to Oxford bone parameters. RESULTS: At 14 years females had femoral diameters of 4.16 +/- 0.23 cm and acetabular diameters of 5.15 +/- 0.30 cm. At 16 years males had femoral diameters of 4.85 +/- 0.30 cm and acetabular diameters of 5.90 +/- 0.35 cm. In the year following maximal femoral Oxford scores, no significant change was seen in femur and acetabulum diameters in females and in femur diameters in males. In the year following maximal acetabular Oxford scores, there was a significant increase in both femur and acetabulum diameters in both females and males. CONCLUSIONS: Females on average reach maximum pelvis maturity at 14 years and males reach maximum pelvis maturity at 16 years. A closed femoral head was found to be a good marker of full hip growth, while a closed triradiate was not. This study provides anatomical data for surgeons to consider in assessing risk factors of THA failure in adolescents.

[An Unusual Reason for Nocturia Combined with Cognitive Decline and Gait Disturbance]. / Nicht alltägliche Ursache der Nykturie bei demenzieller Entwicklung und Gangunsicherheit.

An Unusual Reason for Nocturia Combined with Cognitive Decline and Gait Disturbance Abstract. We present the case of a woman with frequency, nocturia, and painful bladder without urinary incontinence. Further examination showed cognitive decline and gait disturbance. A magnetic resonance imaging of the neurocranium showed normal pressure hydrocephalus. After lumbar puncture with cerebrospinal fluid evacuation the symptoms improved. The clinical triad of gait disturbance, cognitive decline and urinary symptoms like frequency with or without incontinence is typical for normal pressure hydrocephalus (Hakim-Adams triad).

Behavioral and neural processes in counterconditioning: Past and future directions.

Counterconditioning refers both to the technique and putative process by which behavior is modified through a new association with a stimulus of an opposite valence. Similar to extinction, counterconditioning is considered a form of inhibition that interferes with the expression of the originally learned response without erasing it. But whereas interest in extinction continues to rise, counterconditioning has received far less attention. Here, we provide an in-depth review of counterconditioning research and detail whether counterconditioning is any more effective than extinction at preventing relapse of the originally learned behavior. We consider the clinical implications of counterconditioning, describe recent neurobiological and neuroimaging research in this area, and consider future avenues in need of further investigation.

The effects of aversive-to-appetitive counterconditioning on implicit and explicit fear memory.

Counterconditioning (CC) is a form of retroactive interference that inhibits expression of learned behavior. But similar to extinction, CC can be a fairly weak and impermanent form of interference, and the original behavior is prone to relapse. Research on CC is limited, especially in humans, but prior studies suggest it is more effective than extinction at modifying some behaviors (e.g., preference or valence ratings) than others (e.g., physiological arousal). Here, we used a within-subjects design to compare the effects of aversive-to-appetitive CC versus standard extinction on two separate tests of long-term memory in human adults: implicit physiological arousal and explicit episodic memory. Participants underwent Pavlovian fear conditioning to two semantic categories (animals, tools) paired with an electric shock. Conditioned stimuli (i.e., category exemplars) from one category were then extinguished, while stimuli from the other category were paired with a positive outcome. Participants returned 24-h later for a test of skin conductance responses (SCR) to the conditioned exemplars, as well as a surprise recognition memory test for stimuli encoded the previous day. Results showed reduced SCRs at a test for unique stimuli from a category that had undergone CC, relative to stimuli from a category that had undergone standard extinction. Additionally, participants selectively remembered more stimuli encoded during CC than extinction. These results provide new evidence that aversive-to-appetitive CC, as compared to extinction, strengthens memory for items directly associated with a positive outcome, which may provide stronger retrieval competition against a fear memory at test to help diminish fear relapse.

A rare case of Merkel cell carcinoma with ovarian metastasis.

INTRODUCTION: Merkel cell carcinoma (MCC) is a rare cutaneous malignancy that normally occurs in sun-exposed areas of the skin. Risk factors are immundeficency and Merkel cell polyomavirus.Treatment options are surgery, radiotherapy, chemotherapy and immunotherapy in clinical trials. CASE REPORT: We describe a case of an 80-year-old woman with ovarian metastasis of MCC six years after excision of a cutaneous MCC on the cheek. DISCUSSION: To our knowledge only three cases with ovarian metastasis of MCC have been described so far. Our case is the second with distant metastasis to the ovary spreading from a primary tumor in the skin of the head, in the other two cases the primary tumor was in the inguinal skin. CONCULSION: MCC is a highly aggressive cutaneous and mucosal malignancy with frequent recurrence, lymph node and distant metastases. There is no clear consensus how to treat metastatic disease.

A paradigm change to inform fibromyalgia research priorities by engaging patients and health care professionals.

Background: Research objectives should be focused toward advancing knowledge that has meaningful impact on health. However, research agendas are mostly driven by the health care community, with limited input from patients. Aims: In this study, prioirities of uncertainties for the management of fibromyalgia (FM) that could propel future research were identified by a defined process using the James Lind Alliance Priority Setting Partnership (JLA-PSP) methodology. Methods: As a first step, a survey was distributed across Canada that engaged patients, caregivers, and health care professionals to provide narrative input to eight open-ended questions regarding FM care. Responses were thematically condensed and synthesized into an initial list of 43 uncertainties used to guide a comprehensive literature search. Questions already effectively addressed in the literature were excluded, leaving 25 uncertainties that were ranked during a one-day consensus workshop. Results: Three broad themes emerged: the value of personalized targeted treatment and subgrouping of patients; the efficacy of various self-management strategies and educational initiatives; and identification of the ideal health care setting to provide FM care. Opioids and cannabinoids were the only specific pharmacologic interventions ranked as needing further research. Conclusions: The prioritized questions highlight the importance of recognizing the heterogeneity of FM symptoms, the need for a personalized treatment approach, and a better understanding of the value of self-management strategies. This is the first study that uses an established and transparent methodology to engage all FM stakeholders to help inform researchers and funding bodies of clinically relevant research priorities.

Contexte: Les objectifs en matière de recherche devraient se concentrer sur l'avancement des connaissances qui ont des effets significatifs sur la santé. Toutefois, les programmes de recherche sont surtout définis par le milieu des soins de santé, tandis que la contribution des patients demeure limitée.Objectifs: Dans cette étude, les incertitudes prioritaires pour la prise en charge de la fibromylagie, qui pourraient donner lieu à de futures études, ont été déterminées selon un processus fondé sur la méthodologie du Partenariat d'établissement des priorités de la James Lind Alliance.Méthodes: Comme première étape, une enquête a été distribuée partout au Canada auprès de patients, de prestataires de soins et de professionnels de la santé afin d'obtenir leurs réponses sous forme narrative à huit questions ouvertes concernant les soins relatifs à la fibromyalgie. Les réponses ont été regroupées par thèmes et résumées dans une liste initiale de 43 incertitudes qui a été utilisée pour orienter une recherche exhaustive de la littérature. Les questions déjà abordées de manière efficace dans la littérature ont été exclues, tandis que les 25 incertitudes restantes ont été classées dans le cadre d'un atelier de recherche de consensus d'une journée.Résultats: Trois grands thèmes se sont démarqués : l'utilité des traitements ciblés personnalisés et de la division des patients en sous-groupes; l'efficacité de diverses stratégies d'auto-prises en charge et initiatives éducatives; et la détermination du cadre de soins de santé idéal pour dispenser les soins relatifs à la fibromyalgie.Conclusions: Les questions priorisées soulignent l'importance de reconnaître l'hétérogénéité des symptômes de la fibromyalgie, la nécessité d'une approche de traitement personnalisé et une meilleure compréhension de l'utilité des stratégies d'auto-prise en charge. Il s'agit de la première étude à utiliser une méthodologie établie et transparente pour impliquer toutes les parties concernées par la fibromyalgie pour aider à faire connaître aux chercheurs et aux agences de financement les priorités pertinentes sur le plan clinique.

Calcification of the breasts due to loiasis.

A 53-year-old HIV-positive female from Cameroon was diagnosed with loiasis in 2013 due to symptoms of polyarthritis and laboratory confirmed eosinophilia. Because of high microfilaremia primary treatment was given with two courses of albendazol and ivermectin and completed with a course of diethylcarbamazine. Therapy was successful as symptoms, eosinophilia and microfilaremia disappeared. In 2015, she had a gynecology check-up where a screening mammography showed several round and linear, meandering calcifications in both breasts, the latter are typically seen in filariasis.

Determination of arsenic speciation in sulfidic waters by Ion Chromatography Hydride-Generation Atomic Fluorescence Spectrometry (IC-HG-AFS).

A method for the analysis of arsenic species in aqueous sulfide samples is presented. The method uses an ion chromatography system connected with a Hydride-Generation Atomic Fluorescence Spectrometer (IC-HG-AFS). With this method inorganic As(III) and As(V) species in water samples can be analyzed, including arsenite (HnAs(III)O3(n-3)), thioarsenite (HnAs(III)S3(n-3)), arsenate (HnAs(V)O4(n-3)), monothioarsenate (HnAs(V)SO3(n-3)), dithioarsenate (HnAs(V)S2O2(n-3)), trithioarsenate (HnAs(V)S3O(n-3)) and tetrathioarsenate (HnAs(V)S4(n-3)). The peak identification and retention times were determined based on standard analysis of the various arsenic compounds. The analytical detection limit was ~1-3 µg L(-1) (LOD), depending on the quality of the baseline. This low detection limit makes this method also applicable to discriminate between waters meeting the drinking water standard of max. 10 µg L(-1) As, and waters that do not meet this standard. The new method was successfully applied for on-site determination of arsenic species in natural sulfidic waters, in which seven species were unambiguously identified.

Porin alterations present in non-carbapenemase-producing Enterobacteriaceae with high and intermediate levels of carbapenem resistance in Chile.

The main goal of this work was to identify the mechanisms responsible for carbapenem resistance in 61 Chilean clinical isolates of Enterobacteriaceae (Enterobacter spp., Serratia marcescens, Morganella morganii, Escherichia coli and Klebsiella pneumoniae) with reduced susceptibility to at least one carbapenem (ertapenem, imipenem or meropenem). All of the isolates were analysed for the presence of carbapenemases, extended spectrum ß-lactamases (ESBLs), AmpC enzymes and outer-membrane proteins. None of the isolates exhibited carbapenemase activity nor did they have any of the carbapenemase genes that were screened for. Most of the 61 strains produced at least one ESBL and/or one AmpC enzyme and either lost their porins or had altered porins according to sequence analysis. The distribution of ESBLs and AmpC enzymes was different among the species studied. Resistance in K. pneumoniae and E. coli isolates was associated with ESBLs; in M. morganii isolates, resistance was attributed to overexpression of an AmpC enzyme; and in Enterobacter spp. isolates, resistance was associated with both types of enzymes. In K. pneumoniae isolates, porin integrity was more a determinant of carbapenem resistance than the presence of ESBLs, whereas in isolates of Enterobacter spp., M. morganii and S. marcescens, the presence of an overexpressed AmpC enzyme was associated with higher imipenem and meropenem MIC values. Therefore, carbapenem resistance in Chilean isolates is not due to true carbapenemases but rather to a combination of porin loss/alteration and ß-lactamase activity. The fact that carbapenemases were not detected in this study is unique, given that many countries in the region have already reported the presence of these enzymes.

MFGE8 does not influence chorio-retinal homeostasis or choroidal neovascularization in vivo.

PURPOSE: Milk fat globule-epidermal growth factor-factor VIII (MFGE8) is necessary for diurnal outer segment phagocytosis and promotes VEGF-dependent neovascularization. The prevalence of two single nucleotide polymorphisms (SNP) in MFGE8 was studied in two exsudative or "wet" Age-related Macular Degeneration (AMD) groups and two corresponding control groups. We studied the effect of MFGE8 deficiency on retinal homeostasis with age and on choroidal neovascularization (CNV) in mice. METHODS: The distribution of the SNP (rs4945 and rs1878326) of MFGE8 was analyzed in two groups of patients with "wet" AMD and their age-matched controls from Germany and France. MFGE8-expressing cells were identified in Mfge8(+/-) mice expressing ß-galactosidase. Aged Mfge8(+/-) and Mfge8(-/-) mice were studied by funduscopy, histology, electron microscopy, scanning electron microscopy of vascular corrosion casts of the choroid, and after laser-induced CNV. RESULTS: rs1878326 was associated with AMD in the French and German group. The Mfge8 promoter is highly active in photoreceptors but not in retinal pigment epithelium cells. Mfge8(-/-) mice did not differ from controls in terms of fundus appearance, photoreceptor cell layers, choroidal architecture or laser-induced CNV. In contrast, the Bruch's membrane (BM) was slightly but significantly thicker in Mfge8(-/-) mice as compared to controls. CONCLUSIONS: Despite a reproducible minor increase of rs1878326 in AMD patients and a very modest increase in BM in Mfge8(-/-) mice, our data suggests that MFGE8 dysfunction does not play a critical role in the pathogenesis of AMD.