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Obsessive Compulsive Disorder in Palestine: A Literature Review by Israa M.Sawalha in Journal of Clinical Case Reports Medical Images and Health Sciences

Abstract

Methods A computerized literature searches (Google Scholar, PubMed, Science Direct, Springer Link, Elsevier, Semantic Scholar, and HINARI) was used to collect studies addressing the OCD in Palestine.

Results and Conclusion OCD in Palestine is widely presented in adolescence and children at a young age. The most common type of OCD in Palestine is checking type. Set of risk factors increases developing OCD, including sexual abuse at any age as well as anxiety, depression, phobia and somatization disorders. In addition, the family incomes play a big role in presenting OCD, especially low income families. Most of the patients who have OCD were depressed and complaining of stigma and ignorance. Recommendations include getting rid of the stigma, creating a chance for low income families, further studies into OCD in Palestine, ending of the occupation and preventing children from following TV programs and war results.

Key words OCD, Obsessive compulsive disorder, Palestinians Mental Health, Palestine, Gaza Strip, West Bank

Background

In this section the researchers highlighted the meaning of health, mental health and mental illness. Also, they showed the impact of Israeli occupation on Palestinians people since 1948 and lastly in 2019. Besides, the state of mental health services in Palestine. A complete condition of physical, social and mental well-being and not purely disability or disease absence are the definition of the health, according to World Health Organization (WHO)(1). According to American Psychiatric Association (APA) the mental health is the foundation for learning, communication, emotions, thinking, self-esteem and resilience, also, it is the key to personal and emotional well-being, relationships, personal and contributing to the community or society(2). Therefore, the combination of behavioral, emotional or thinking process changes, or involving a change in one of them is called a mental health illness which is common and can be treatable(3). Historically, Palestinians health affected because of the Israeli occupation of Palestine, which was divided into two areas (West Bank and Gaza Strip)(4). Those two areas were occupied by Israel in 1948, related to that about 60 percent of the Palestinians living in villages with 27 percent of them in refugee camps(5). Accordingly, Israel attacks the civilians in their places and they experience infringement of their human rights which impact their health(6). Because of affection on the civilian health, especially the mental health, there is a need to develop mental health services(7). Therefore, in 2004 the mental health policy officially adopted for West Bank and Gaza Strip by Palestinian Ministry of Health (MoH) and in 2002-2003 it was formulated(5). As a result, Palestinians need to meet them human rights and develop the mental health policies and services(8). In summary, the history that the researchers mentioned above about Palestine’s political condition, clearly showed that there are major challenges faced the civilians’ mental health, as well as, their social and economic state.

Methodology

A computerized literature searches (Google Scholar, PubMed, Science Direct, Springer Link, Elsevier, Semantic Scholar, and HINARI) was used to collect studies addressing the OCD in Palestine. Search terms included “obsessive-compulsive disorder,” “obsessive compulsive” “OCD Palestine” “Palestinians mental health” “Health in Palestine” “Mental health Palestine” in both Arabic and English languages. Additional papers, which did not appear clearly in the electronic database while searching, were obtained via an examination of reference lists of published papers. Relevant empirical studies are summarized and presented hither. This study included all studies about OCD in Palestine and excluded the studies talked about anxiety, PTSD, or other disorders. The search identified 33 articles. Duplicates and irrelevant articles were removed. Nine articles related to OCD in a Worldwide, fifteen in Arabic countries and nine articles related to OCD in West Bank and Gaza Strip in Palestine. Also the researcher used some Arabic studies and translated them to English language. Studies selected after critically appraised.

An overview of OCD

In this following section the researchers explained the origin of Obsessive Compulsive Disorder (OCD) by writing its definition and clarified main class of OCD and from where it came. Also, this review showed studies about mental health in a worldwide then Arabic world later in Palestine. Moreover, the following sections focused on OCD in Palestine.

Definition of Obsessive Compulsive Disorder This part of the study focused on the definition of Obsessive Compulsive Disorder as both of the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) defined it. According to ICD-10, the essential feature of OCD is recurrent Obsessional thoughts and Compulsive act(9), but according to DSM-5, OCD is the presence of obsessions, compulsions, or both of them(10). Obsessional thoughts are images, impulses, or ideas that enter the patient's mind repeatedly in a vulgar form. They are almost fixedly distressing and the patient often tries, unsuccessfully, to endure them, this definition according to ICD-10(9). But DSM-5 defined the Obsessional thoughts as an intruder, unwanted and recurrent thoughts or impulses that most patients cause marked anxiety or distress and the patient trials to ignore such thoughts or images by performing a Compulsion(10). Additionally, ICD-10 about Compulsive, an acts or rituals are stereotyped behaviors that are repeated over and over, these acts are not enjoyable, nor do they result in the completion of useful tasks(9). Also, the repetitive behaviors (e.g., hand washing, ordering, checking) or mental acts (e.g., praying, counting, repeating words silently) is aimed at preventing or reducing anxiety or distress, or preventing some dreaded event or situation, this definition according to DSM-5(10). As the researchers mentioned above, the OCD is a mental health disorder associated with a change in behaviors and acts, as well as with thoughts changes.

History of Obsessive Compulsive Disorder

In this part the researchers showed the historical sequence of Obsessive Compulsive Disorder. Al-Balakhi was the first one in the world mentioned a mental illness and he put the differentiation of OCD from other forms of mental illnesses nearly a millennium earlier(11). Historically, as with any mental health condition, over time the conceptualization and treatment of OCD has changed(12). In the centuries sixteenth, seventeenth, eighteenth, nineteenth and the first half of the twentieth century the OCD passed through different conceptualizations. Religious melancholy was in seventeenth century the description of Obsession and Compulsion(13), but they have likely been around since humans first roved the earth(12). OCD was associated with moral and spiritual issue in the seventeenth century. Later, in eighteenth century many doctors saw that the Obsessions and Compulsions were caused by intellectual disordered(12).After this view, in the nineteenth century a modern concepts of OCD began to evolved(14),which is ‘neurosis’ implied a neuropathological condition. In the last quarter of the nineteenth century OCD was engulfed along with numerous other disorders(13). Supplementally, in the twentieth century the OCD became with a new concept. Sigmund Freud (1856-1939) and Pierre Janet (1859-1947) isolated OCD from neurasthenia(14).Freud’s view highlighted that this mental health disorder related to subconscious problems, and he sawed that both of obsessions and compulsions were often treated via psychoanalysis(14). Throughout the first half of the twentieth century Freud’s view dominated the mental health field(13). Finally, the researchers back in the time since the appearance of Obsessive Compulsive Disorder until the new concept were appeared.

OCD in a worldwide

In this section the researchers showed a review of OCD from the worldwide view by showing the prevalence of OCD in a worldwide, also the effect of it on the patient’s life, as well as its types and the prevalence of each one. Later the researchers showed risk factors. In the world, at some points in peoples’ lives, they have obsessive thoughts with or without compulsive behaviors, but that does not mean that all of them suffer from Obsessive Compulsive Disorder(15). Approximately 2% is the prevalence of in the general population in a worldwide(16). During the past year, OCD in the U.S affected 1.2% of adults. But now it affects approximately 1 in 40 adults and 1 in 100 children in the U.S. According to the National Institute of Mental Health (NIMH)(17). In Australia around 2% of people have OCD(18). But in the UK population, OCD affects about 12 in every 1,000 people (1.2% of the population) from young children to adults, regardless of social, cultural background or gender(19). In China the prevalence of OCD is 3.17%, according to a study done by Guo et al., its title is “Meta-analysis of the prevalence of anxiety disorders in mainland China from 2000 to 2015”(20). In this condition the patient has an obsessive need to repeatedly do certain things and may have unwanted ideas, impulses or images(21). People with OCD are usually aware that their symptoms are illogical and excessive, but they find the obsessions ungovernable and the compulsions unattainable to resist(18). There are many forms of OCD, Checking, Contamination/Mental Contamination, Symmetry and ordering, Ruminations/Intrusive thoughts and Hording(22). About the prevalence of each type the checking obsessive has the highest prevalence which is 79.3%, the second high prevalence is Hoarding obsessive which has 62.3%, later Ordering 3%, Morality 5%, Sexual/Religious 2%, Contamination/Washing 3%, Harming/Aggression 5% and Illness ratios 8% to 10% (23). A study done by J. Henderson and C. Pollard in greater ST. Louis showed that the overall prevalence rate of OCD was 2.8%. The most prevalent type of Obsessive Compulsive Disorder involved checking (1.6%), followed by a multiple category that included counting, repeating and collecting rituals (1.0%) and, finally, washing compulsions (0.8%)(24) According to National Comorbidity Survey Replication (NCS-R), many people with Obsessive Compulsive Disorder have more than one OCD form(23). The risk factors which may increase the incidence of getting an OCD are divided into three ranks, factors that the person born with, factors outside human control and modifiable risk factors(25). Factors person born with like genetics 50%, gender male at more risk to develop childhood OCD than female, brain structure and socioeconomic status as a study showed that there is an association between OCD and low socioeconomic status(25). But about the factors outside human control are included age life events and mental illness. The risk of OCD drops with age and the late adolescence has the greater risk(25). Those who have stressful life and suffer from physical or sexual abuse are a major risk factor to get OCD, also having another mental illness such as anxiety or depression increase the risk of having OCD (26). According to Owen and Adrian, the third rank is the modifiable risk factors such as drugs, marital status and employment. Drug uses cans causing a neurotransmitter changes in the brain, which create a chance for developing OCD, and being unmarried increase the risk too as well as being unemployed. However, there are many risk factors may increase the incidence to develop an OCD. OCD at higher risk to present comorbid major depression or another anxiety disorder across all areas(27). Peoples suffering from OCD also end up suffering from a lack of self-esteem and self-confidence, relationship problems, very weak willpower, and social withdrawal(28).

OCD in the Arabic countries

In this section the researchers showed a review about OCD in Arabic countries. From one hand, they pointed out that the first one highlighted the OCD was an Arabian psychiatrist and he wrote about it since 1000 years ago. And from other hand, they reviewed different studies about OCD prevalence, Islamic view, culture view and stigma in the Arabic world. Statistics mentioned that the frequency of most mental disorders does not have much difference from country to country around the world(32). The prevalence of OCD in Egyptian adolescent population is 2.2%(33). Also, 0.1 % in Lebanon(34). In Iraq, the peak age for OCD was from 21 to 30 years old, females were predominating (63.2%), singles were (47.3%) and the family history of OCD and any mental illness was observed in 20.5% and 52.9%, respectively(35). The few statistics coming out of certain Arab countries assert the reality of having no difference from country to country in the frequency of mental disorders specially OCD(32). The issue in the Arab world is more to do with stigma and ignorance than it is lack of mental health problems(32). Despite the complication and the importance of the mental health problems, the Arab world still shows a lack of awareness; patients in Arab countries tend to express their psychological issues in terms of physical symptoms, thereby avoiding the stigma attached to mental illness(36). A study done by Mohamed et al., 2015 in Egypt showed the following result: “Religious patients receiving religious psychotherapy showed significantly more rapid improvement and required lower dosage of medications and for periods less than others. The role of religion as CBT could be significant in the Islamic culture.”(37). Recently, the relationship between mental health, religiosity, and personal beliefs (Such as magical ideation) has been studied Psychiatry is depending on culture more than any other medical discipline, therefore, it is not well known in developing countries the frequency of mental illness such as anxiety, OCD or depression, even doctors themselves may not know the problem size, on the contrary of the developed countries which are well characterized in determining mental diseases(32).

An overview of OCD in Palestine

In this section the researchers showed a review of OCD in Palestine. They mentioned the prevalence of OCD in Palestine, and showed the all available studies about OCD. A 15.3% is the prevalence of Obsessive Compulsive Disorder among Palestinian university students in Gaza Strip, in assessing OCD and sociodemographic variables such as family income and type of college, study showed that the OCD is more in students coming from families earning 250$ and leases more than students from families earning 500-750$ and there is no statistical significant in OCD and type of college. In addition to that, this study showed there is no statistically significant correlation between OCD and age and grade average of the students. Also, this study clarifies that the OCD correlate with anxiety (R=0.63), with depression (R=0.66, P=0.001), with Phobic anxiety (R=0.44) and with Somatization (R=0.51). However, in assessing the OCD statue with sex, the T independent test according to the same study showed statistically significant in female than in male (Mean 15.39 vs. 15.20) (T= -50)(39). Additionally, a descriptive study done by Amira Abu Shaban in Jerusalem zone by using self-reported questionnaire and the Yale-Brown Obsessive Compulsive Scale (CY-BOCS) among Palestinian school children grade 11 (public and private), this study showed that the prevalence of OCD among Palestinian school students is 15.6%: 19.1 for females and 10.2 for males. Also, the study showed significant associations among OCD and females, students with low academic level, school achievements and less educated parents. Moreover, this study showed a strong relationship between OCD and social-demographic variables and a weak relationship with social environmental factors(40). 20.6%, according to Spence anxiety scale reported Obsessive Compulsive Disorder problems among children working due to low family income. This study, which was done by Mater et al (2007), aimed to identify the impact of work on children general mental health and anxiety in a total number of 789 children in the Gaza Strip. Also, it showed that 79.2% of children rating themselves as a psychiatric patient(42). The study sample included 99 women and their ages ranged between 16 years to 42 years with mean age 25.5. In this study pre and post assessment for women who got counseling and vocational training. Accordingly, the study showed that there was improvement in Obsessive Compulsive Disorder for the women(45). In the summary for the OCD in Palestine, the OCD is higher in women than men, in adolescent and children than older ages. The risk factors that increase the OCD separation between Palestinians are low income families, stigma, and Israeli occupation, and violence, sexual abuse of the children, depression disorder and anxiety disorder.

Discussion

In this section the researchers discussed the reviewed studies about OCD worldwide, in Arabic countries, and in Palestine by showing the differences in prevalence, stigma, and risk factors.

Prevalence

The studies showed that the prevalence of OCD in a worldwide is 2%-3% (16) Convergent to the prevalence in Arabic countries 2.2% (32), but there is no general prevalence of OCD in Palestine because of lack in studies. But some studies showed 15.3% the prevalence of Obsessive Compulsive Disorder among Palestinian university students in Gaza Strip (16, 32). Checking Obsessive is the most common type in the world, 79.3% of the OCD patients are checking obsessively and 62.3% suffer from Hording Obsessive (23). The studies in Arabic countries also support this prevalence of checking obsessive 1.6%, then hording then contamination obsessions (23, 22), after that the contamination obsessions in Arabic countries and in Palestine (22, 34).

Stigma

The issue in the Arab world is more to do with stigma and ignorance than it is lack of mental health problems and the stigma attached to the illness (34, 35). Also the Palestinians studies showed that the patients suffer from community view to them and their mental health (38). The Arab world still shows a lack of awareness; patients in Arab countries tend to express their psychological issues in terms of physical symptoms, thereby avoiding the stigma attached to mental illness (36).

The risk factors

The risk factor which may increase the incidence of getting an OCD are divided into three ranks, factors that the person born with, factors outside human control and modifiable risk factors (26). The genetic factor prevalence is 50% and the male more than female in childhood (25, 28) in the world view, but in comparison with Arabic countries view the risk factors were in female more than in male in ages between 21 to 30 years old (34, 31) . Finally, in Palestine the low family income earning 250$ and less were the basis for having an OCD among Palestinians, also the studies in Palestine showed that the female more than male with mean age 15.39 for female Verses 15.20 for male(38, 31). In addition to the OCD risk factor in Palestine the sexual abuse at any age play a major role in having OCD as well as Anxiety, depression, Phobic anxiety and Somatization disorders (31, 38, 40, 44).

Definition

They are almost fixedly distressing and the patient often tries, unsuccessfully, to endure them while DSM-5 defined the Obsessional thoughts as an intruder, unwanted and recurrent thoughts or impulses that most patients cause marked anxiety or distress and the patient trials to ignore such thoughts or images by performing a Compulsion (15).

Results and Conclusion

In this section, the researchers conclude the results of this review. According to the studies that the researchers reviewed and discussed above, they found that there is a difference between the prevalence of OCD in Palestine in comparing with Arabic countries as well as with a worldwide. Also, they discovered that there is a lack of studies about OCD in Palestine especially in West Bank. The most common type of OCD in Palestine is checking type; in addition to that, OCD patients suffer from the stigma so the prevalence of it was significantly high related to fear from the community. However, there is a religious view about OCD as well as cultural view. Palestinians because of Israel occupation faced a lot of barriers standing in front of their mental health status. OCD in Palestine is widely presented in adolescence and children at a young age. The family incomes play a big role in present of OCD, especially low income families as well as a stigma. In concluding, Palestinians with OCD have a related disorder, the most common one is depressed. Also the researchers found that there was a lack in studies about OCD in Palestine and other mental health disorders, and they discovered that there is a study in specific areas of Palestine such as Gaza Strip

Recommendations

Recommendations include get rid of the stigma and create a work chances for a low income family, apply more and more studies about OCD in Palestine, ending of the occupation and prevent the children from following TV programs and war.

Limitations

The literature review has discussed an Obsessive Compulsive Disorder in Palestine. Palestine is a state that is seeking independence with a scare of resources; therefore, the research is underdeveloped. As a result, there is a lack of detailed data regarding Obsessive Compulsive Disorder in Palestine. Due to lack the complete data, all literature that was found, including a thesis study done in Al-Quds Open University about the OCD among school students in 11 grade was included.

Acknowledgments

Special thanks to all authors in the field of mental health in Palestine who equipped us with the relevant information for this literature.

This case represents an unusual example of extrinsic esophageal compression due to lymphoma1,2 leading to severe pill- induced esophagitis3.

#OCD #Obsessive compulsive disorder #Gaza Strip #JCRMHS #West Bank #Palestinians Mental Health #Journal of Clinical Case Reports Medical Images and Health Sciences quartile #Palestine

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myrawjcsmicasereports · 1 month ago

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Inhibition of EIF4E Downregulates VEGFA and CCND1 Expression to Suppress Ovarian Cancer Tumor Progression by Jing Wang in Journal of Clinical Case Reports Medical Images and Health Sciences

Abstract

This study investigates the role of EIF4E in ovarian cancer and its influence on the expression of VEGFA and CCND1. Differential expression analysis of VEGFA, CCND1, and EIF4E was conducted using SKOV3 cells in ovarian cancer patients and controls. Correlations between EIF4E and VEGFA/CCND1 were assessed, and three-dimensional cell culture experiments were performed. Comparisons of EIF4E, VEGFA, and CCND1 mRNA and protein expression between the EIF4E inhibitor 4EGI-1-treated group and controls were carried out through RT-PCR and Western blot. Our findings demonstrate elevated expression of EIF4E, VEGFA, and CCND1 in ovarian cancer patients, with positive correlations. The inhibition of EIF4E by 4EGI-1 led to decreased SKOV3 cell clustering and reduced mRNA and protein levels of VEGFA and CCND1. These results suggest that EIF4E plays a crucial role in ovarian cancer and its inhibition may modulate VEGFA and CCND1 expression, underscoring EIF4E as a potential therapeutic target for ovarian cancer treatment.

Keywords: Ovarian cancer; Eukaryotic translation initiation factor 4E; Vascular endothelial growth factor A; Cyclin D1

Introduction

Ovarian cancer ranks high among gynecological malignancies in terms of mortality, necessitating innovative therapeutic strategies [1]. Vascular endothelial growth factor (VEGF) plays a pivotal role in angiogenesis, influencing endothelial cell proliferation, migration, vascular permeability, and apoptosis regulation [2, 3]. While anti-VEGF therapies are prominent in malignancy treatment [4], the significance of cyclin D1 (CCND1) amplification in cancers, including ovarian, cannot be overlooked, as it disrupts the cell cycle, fostering tumorigenesis [5, 6]. Eukaryotic translation initiation factor 4E (EIF4E), central to translation initiation, correlates with poor prognoses in various cancers due to its dysregulated expression and activation, particularly in driving translation of growth-promoting genes like VEGF [7, 8]. Remarkably, elevated EIF4E protein levels have been observed in ovarian cancer tissue, suggesting a potential role in enhancing CCND1 translation, thereby facilitating cell cycle progression and proliferation [9]. Hence, a novel conjecture emerges: by modulating EIF4E expression, a dual impact on VEGF and CCND1 expression might be achieved. This approach introduces an innovative perspective to impede the onset and progression of ovarian cancer, distinct from existing literature, and potentially offering a unique therapeutic avenue.

Materials and Methods

Cell Culture

Human ovarian serous carcinoma cell line SKOV3 (obtained from the Cell Resource Center, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences) was cultured in DMEM medium containing 10% fetal bovine serum. Cells were maintained at 37°C with 5% CO2 in a cell culture incubator and subcultured every 2-3 days.

Three-Dimensional Spheroid Culture

SKOV3 cells were prepared as single-cell suspensions and adjusted to a concentration of 5×10^5 cells/mL. A volume of 0.5 mL of single-cell suspension was added to Corning Ultra-Low Attachment 24-well microplates and cultured at 37°C with 5% CO2 for 24 hours. Subsequently, 0.5 mL of culture medium or 0.5 mL of EIF4E inhibitor 4EGI-1 (Selleck, 40 μM) was added. After 48 hours, images were captured randomly from five different fields—upper, lower, left, right, and center—using an inverted phase-contrast microscope. The experiment was repeated three times.

GEPIA Online Analysis

The GEPIA online analysis tool (http://gepia.cancer-pku.cn/index.html) was utilized to assess the expression of VEGFA, CCND1, and EIF4E in ovarian cancer tumor samples from TCGA and normal samples from GTEx. Additionally, Pearson correlation coefficient analysis was employed to determine the correlation between VEGF and CCND1 with EIF4E.

RT-PCR

RT-PCR was employed to assess the mRNA expression levels of EIF4E, VEGF, and CCND1 in treatment and control group samples. Total RNA was extracted using the RNA extraction kit from Vazyme, followed by reverse transcription to obtain cDNA using their reverse transcription kit. Amplification was carried out using SYBR qPCR Master Mix as per the recommended conditions from Vazyme. GAPDH was used as an internal reference, and the primer sequences for PCR are shown in Table 1.

Amplification was carried out under the following conditions: an initial denaturation step at 95°C for 60 seconds, followed by cycling conditions of denaturation at 95°C for 10 seconds, annealing at 60°C for 30 seconds, repeated for a total of 40 cycles. Melting curves were determined under the corresponding conditions. Each sample was subjected to triplicate experiments. The reference gene GAPDH was used for normalization. The relative expression levels of the target genes were calculated using the 2-ΔΔCt method.

Western Blot

Western Blot technique was employed to assess the protein expression levels of EIF4E, VEGF, and CCND1 in the treatment and control groups. Initially, cell samples collected using RIPA lysis buffer were lysed, and the total protein concentration was determined using the BCA assay kit (Shanghai Biyuntian Biotechnology, Product No.: P0012S). Based on the detected concentration, 20 μg of total protein was loaded per well. Electrophoresis was carried out using 5% stacking gel and 10% separating gel. Subsequently, the following primary antibodies were used for immune reactions: rabbit anti-human polyclonal antibody against phospho-EIF4E (Beijing Boao Sen Biotechnology, Product No.: bs-2446R, dilution 1:1000), mouse anti-human monoclonal antibody against EIF4E (Wuhan Sanying Biotechnology, Product No.: 66655-1-Ig, dilution 1:5000), mouse anti-human monoclonal antibody against VEGFA (Wuhan Sanying Biotechnology, Product No.: 66828-1-Ig, dilution 1:1000), mouse anti-human monoclonal antibody against CCND1 (Wuhan Sanying Biotechnology, Product No.: 60186-1-Ig, dilution 1:5000), and mouse anti-human monoclonal antibody against GAPDH (Shanghai Biyuntian Biotechnology, Product No.: AF0006, dilution 1:1000). Subsequently, secondary antibodies conjugated with horseradish peroxidase (Shanghai Biyuntian Biotechnology, Product No.: A0216, dilution 1:1000) were used for immune reactions. Finally, super-sensitive ECL chemiluminescence reagent (Shanghai Biyuntian Biotechnology, Product No.: P0018S) was employed for visualization, and the ChemiDocTM Imaging System (Bio-Rad Laboratories, USA) was used for image analysis.

Statistical Analysis

GraphPad software was used for statistical analysis. Data were presented as (x ± s) and analyzed using the t-test for quantitative data. Pearson correlation analysis was performed for assessing correlations. A significance level of P < 0.05 was considered statistically significant.

Results

3D Cell Culture of SKOV3 Cells and Inhibitory Effect of 4EGI-1 on Aggregation

In this experiment, SKOV3 cells were subjected to 3D cell culture, and the impact of the EIF4E inhibitor 4EGI-1 on ovarian cancer cell aggregation was investigated. As depicted in Figure 1, compared to the control group (Figure 1A), the diameter of the SKOV3 cell spheres significantly decreased in the treatment group (Figure 1B) when exposed to 4EGI-1 under identical culture conditions. This observation indicates that inhibiting EIF4E expression effectively suppresses tumor aggregation.

Expression and Correlation Analysis of VEGFA, CCND1, and EIF4E in Ovarian Cancer Samples

To investigate the expression of VEGFA, CCND1, and EIF4E in ovarian cancer, we utilized the GEPIA online analysis tool and employed the Pearson correlation analysis method to compare expression differences between tumor and normal groups. As depicted in Figures 2A-C, the results indicate significantly elevated expression levels of VEGFA, CCND1, and EIF4E in the tumor group compared to the normal control group. Notably, the expression differences of VEGFA and CCND1 were statistically significant (p < 0.05). Furthermore, the correlation analysis revealed a positive correlation between VEGFA and CCND1 with EIF4E (Figures 2D-E), and this correlation exhibited significant statistical differences (p < 0.001). These findings suggest a potential pivotal role of VEGFA, CCND1, and EIF4E in the initiation and progression of ovarian cancer, indicating the presence of intricate interrelationships among them.

EIF4E, VEGFA, and CCND1 mRNA Expression in SKOV3 Cells

To investigate the function of EIF4E in SKOV3 cells, we conducted RT-PCR experiments comparing EIF4E inhibition group with the control group. As illustrated in Figure 3, treatment with 4EGI-1 significantly reduced EIF4E expression (0.58±0.09 vs. control, p < 0.01). Concurrently, mRNA expression of VEGFA (0.76±0.15 vs. control, p < 0.05) and CCND1 (0.81±0.11 vs. control, p < 0.05) also displayed a substantial decrease. These findings underscore the significant impact of EIF4E inhibition on the expression of VEGFA and CCND1, indicating statistically significant differences.

Protein Expression Profiles in SKOV3 Cells with EIF4E Inhibition and Control Group

Protein expression of EIF4E, VEGFA, and CCND1 was assessed using Western Blot in the 4EGI-1 treatment group and the control group. As presented in Figure 4, the expression of p-EIF4E was significantly lower in the 4EGI-1 treatment group compared to the control group (0.33±0.14 vs. control, p < 0.001). Simultaneously, the expression of VEGFA (0.53±0.18 vs. control, p < 0.01) and CCND1 (0.44±0.16 vs. control, p < 0.001) in the 4EGI-1 treatment group exhibited a marked reduction compared to the control group.

Discussion

EIF4E is a post-transcriptional modification factor that plays a pivotal role in protein synthesis. Recent studies have underscored its critical involvement in various cancers [10]. In the context of ovarian cancer research, elevated EIF4E expression has been observed in late-stage ovarian cancer tissues, with low EIF4E expression correlating to higher survival rates [9]. Suppression of EIF4E expression or function has been shown to inhibit ovarian cancer cell proliferation, invasion, and promote apoptosis. Various compounds and drugs that inhibit EIF4E have been identified, rendering them potential candidates for ovarian cancer treatment [11]. Based on the progressing understanding of EIF4E's role in ovarian cancer, inhibiting EIF4E has emerged as a novel therapeutic avenue for the disease. 4EGI-1, a cap-dependent translation small molecule inhibitor, has been suggested to disrupt the formation of the eIF4E complex [12]. In this study, our analysis of public databases revealed elevated EIF4E expression in ovarian cancer patients compared to normal controls. Furthermore, through treatment with 4EGI-1 in the SKOV3 ovarian cancer cell line, we observed a capacity for 4EGI-1 to inhibit SKOV3 cell spheroid formation. Concurrently, results from PCR and Western Blot analyses demonstrated effective EIF4E inhibition by 4EGI-1. Collectively, 4EGI-1 effectively suppresses EIF4E expression and may exert its effects on ovarian cancer therapy by modulating EIF4E.

Vascular Endothelial Growth Factor (VEGF) is a protein that stimulates angiogenesis and increases vascular permeability, playing a crucial role in tumor growth and metastasis [13]. In ovarian cancer, excessive release of VEGF by tumor cells leads to increased angiogenesis, forming a new vascular network to provide nutrients and oxygen to tumor cells. The formation of new blood vessels enables tumor growth, proliferation, and facilitates tumor cell dissemination into the bloodstream, contributing to distant metastasis [14]. As a significant member of the VEGF family, VEGFA has been extensively studied, and it has been reported that VEGFA expression is notably higher in ovarian cancer tumors [15], consistent with our public database analysis. Furthermore, elevated EIF4E levels have been associated with increased malignant tumor VEGF mRNA translation [16]. Through the use of the EIF4E inhibitor 4EGI-1 in ovarian cancer cell lines, we observed a downregulation in both mRNA and protein expression levels of VEGFA. This suggests that EIF4E inhibition might affect ovarian cancer cell angiogenesis capability through downregulation of VEGF expression.

Cyclin D1 (CCND1) is a cell cycle regulatory protein that participates in controlling cell entry into the S phase and the cell division process. In ovarian cancer, overexpression of CCND1 is associated with increased tumor proliferation activity and poor prognosis [17]. Elevated CCND1 levels promote cell cycle progression, leading to uncontrolled cell proliferation [18]. Additionally, CCND1 can activate cell cycle-related signaling pathways, promoting cancer cell growth and invasion capabilities [19]. Studies have shown that CCND1 gene expression is significantly higher in ovarian cancer tissues compared to normal ovarian tissues [20], potentially promoting proliferation and cell cycle progression through enhanced cyclin D1 translation [9]. Our public database analysis results confirm these observations. Furthermore, treatment with the EIF4E inhibitor 4EGI-1 in ovarian cancer cell lines resulted in varying degrees of downregulation in CCND1 mRNA and protein levels. This indicates that EIF4E inhibition might affect ovarian cancer cell proliferation and cell cycle progression through regulation of CCND1 expression.

In conclusion, overexpression of EIF4E appears to be closely associated with the clinical and pathological characteristics of ovarian cancer patients. In various tumors, EIF4E is significantly correlated with VEGF and cyclin D1, suggesting its role in the regulation of protein translation related to angiogenesis and growth [9, 21]. The correlation analysis results in our study further confirmed the positive correlation among EIF4E, VEGFA, and CCND1 in ovarian cancer. Simultaneous inhibition of EIF4E also led to downregulation of VEGFA and CCND1 expression, validating their interconnectedness. Thus, targeted therapy against EIF4E may prove to be an effective strategy for treating ovarian cancer. However, further research and clinical trials are necessary to assess the safety and efficacy of targeted EIF4E therapy, offering more effective treatment options for ovarian cancer patients.

Acknowledgments:

Funding: This study was supported by the Joint Project of Southwest Medical University and the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University (Grant No. 2020XYLH-043).

Conflict of Interest: The authors declare no conflicts of interest.

#Ovarian cancer #Eukaryotic translation initiation factor 4E #Vascular endothelial growth factor A #Cyclin D1 #Review Article in Journal of Clinical Case Reports Medical Images and Health Sciences .#jcrmhs

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biomedres · 2 days ago

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Pathogenic Microorganism Detection in Invasive Pulmonary Aspergillosis(IPA) Patients Using Bronchoalveolar Lavage Fluid

Pathogenic Microorganism Detection in Invasive Pulmonary Aspergillosis(IPA) Patients Using Bronchoalveolar Lavage Fluid in Biomedical Journal of Scientific & Technical Research

Background: To evaluate the diagnostic values of different forms of pathogenic microorganism detection from the bronchoalveolar lavage fluid (BALF) for Invasive Pulmonary Aspergillosis (IPA) diagnosis.

Methods: Bronchoalveolar lavage fluid (BALF) was collected from 100 patients with suspected clinical pulmonary Aspergillus infections by means of bronchoscopy. The smear microscopy, fungal culture and PCR were used to detect the Aspergillus from the BALF.

Results: 15 cases were diagnosed by pathological data(the proven group), while 12 confirmed cases were supported by clinical examinations including radiology and etiology (the probable group). The 73 cases left were not IPA, among which 21 cases of common pneumonia were taken as the control group. For the practise of smear microscopy method, the sensitivity, specificity, and accuracy of the diagnoses were 40.7%, 100.0%, and 66.7% respectively. As for the fungal culture, the sensitivity, specificity, and accuracy were 37.0%,100.0%, and 64.6% respectively. For PCR, the sensitivity, specificity, and accuracy were 55.6%, 100.0%, and 77.1% respectively. With the combination of the three methods mentioned, the final results were 92.6%, 100.0% and 95.8%.

Conclusion: The pathogenic detection of bronchoalveolar lavage fluid (BALF) is an ideal diagnostic method for Aspergillus infections. The smear microscopy method, the fungal culture and PCR has their own limitations in diagnosis. The detection of combining the three methods is proved to improve the efficiency of IPA diagnosis significantly.

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jcrmhscasereports · 1 year ago

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Retinal and choroidal vascular drop out in a case of severe phenotype of Flammer Syndrome. Rescue of the ischemic-preconditioning mimicking action of endogenous Erythropoietin (EPO) by off-label intra vitreal injection of recombinant human EPO (rhEPO) by Claude Boscher in Journal of Clinical Case Reports Medical Images and Health Sciences

Journal of Clinical Case Reports Medical Images and Health Sciences

ABSTRACT

Background: Erythropoietin (EPO) is a pleiotropic anti-apoptotic, neurotrophic, anti-inflammatory, and pro-angiogenic endogenous agent, in addition to its effect on erythropoiesis. Exogenous EPO is currently used notably in human spinal cord trauma, and pilot studies in ocular diseases have been reported. Its action has been shown in all (neurons, glia, retinal pigment epithelium, and endothelial) retinal cells. Patients affected by the Flammer Syndrome (FS) (secondary to Endothelin (ET)-related endothelial dysfunction) are exposed to ischemic accidents in the microcirculation, notably the retina and optic nerve.

Case Presentation: A 54 years old female patient with a diagnosis of venous occlusion OR since three weeks presented on March 3, 2019. A severe Flammer phenotype and underlying non arteritic ischemic optic neuropathy; retinal and choroidal drop-out were obviated. Investigation and follow-up were performed for 36 months with Retinal Multimodal Imaging (Visual field, SD-OCT, OCT- Angiography, Indo Cyanin Green Cine-Video Angiography). Recombinant human EPO (rhEPO)(EPREX®)(2000 units, 0.05 cc) off-label intravitreal injection was performed twice at one month interval. Visual acuity rapidly improved from 20/200 to 20/63 with disparition of the initial altitudinal scotoma after the first rhEPO injection, to 20/40 after the second injection, and gradually up to 20/32, by month 5 to month 36. Secondary cystoid macular edema developed ten days after the first injection, that was not treated via anti-VEGF therapy, and resolved after the second rhEPO injection. PR1 layer integrity, as well as protective macular gliosis were fully restored. Some level of ischemia persisted in the deep capillary plexus and at the optic disc.

Conclusion: Patients with FS are submitted to chronic ischemia and paroxystic ischemia/reperfusion injury that drive survival physiological adaptations via the hypoxic-preconditioning mimicking effect of endogenous EPO, that becomes overwhelmed in case of acute hypoxic stress threshold above resilience limits. Intra vitreal exogenous rhEPO injection restores retinal hypoxic-preconditioning adaptation capacity, provided it is timely administrated. Intra vitreal rhEPO might be beneficial in other retinal diseases of ischemic and inflammatory nature.

Key words : Erythropoietin, retinal vein occlusion, anterior ischemic optic neuropathy, Flammer syndrome, Primary Vascular Dysfunction, anti-VEGF therapy, Endothelin, microcirculation, off-label therapy.

INTRODUCTION

Retinal Venous Occlusion (RVO) treatment still carries insufficiencies and contradictions (1) due to the incomplete deciphering of the pathophysiology and of its complex multifactorial nature, with overlooking of factors other than VEGF up-regulation, notably the roles of retinal venous tone and Endothelin-1 (ET) (2-5), and of endothelial caspase-9 activation (6). Flammer Syndrome (FS)( (Primary Vascular Dysfunction) is related to a non atherosclerotic ET-related endothelial dysfunction in a context of frequent hypotension and increased oxidative stress (OS), that alienates organs perfusion, with notably changeable functional altered regulation of blood flow (7-9), but the pathophysiology remains uncompletely elucidated (8). FS is more frequent in females, and does not seem to be expressed among outdoors workers, implying an influence of sex hormons and light (7)(9). ET is the most potent pro-proliferative, pro-fibrotic, pro-oxidative and pro-inflammatory vasoconstrictor, currently considered involved in many diseases other than cardio-vascular ones, and is notably an inducer of neuronal apoptosis (10). It is produced by endothelial (EC), smooth vascular muscles (SVMC) and kidney medullar cells, and binds the surface Receptors ET-A on SVMC and ET-B on EC, in an autocrine and paracrine fashion. Schematically, binding on SVMC Receptors (i.e. through local diffusion in fenestrated capillaries or dysfunctioning EC) and on EC ones (i.e. by circulating ET) induce respectively arterial and venous vasoconstriction, and vasodilation, the latter via Nitrite oxide (NO) synthesis. ET production is stimulated notably by Angiotensin 2, insulin, cortisol, hypoxia, and antagonized by endothelial gaseous NO, itself induced by flow shear stress. Schematically but not exclusively, vascular tone is maintained by a complex regulation of ET-NO balance (8) (10-11). Both decrease of NO and increase of ET production are both a cause and consequence of inflammation, OS and endothelial dysfunction, that accordingly favour vasoconstriction; in addition ET competes for L-arginine substrate with NO synthase, thereby reducing NO bioavailability, a mechanism obviated notably in carotid plaques and amaurosis fugax (reviewed in 11).

Severe FS phenotypes are rare. Within the eye, circulating ET reaches retinal VSMC in case of Blood-Retinal-Barrier (BRB) rupture and diffuses freely via the fenestrated choroidal circulation, notably around the optic nerve (ON) head behind the lamina cribrosa, and may induce all pathologies related to acute ocular blood flow decrease (2-3)(5)(7-9). We previously reported two severe cases with rapid onset of monocular cecity and low vision, of respectively RVO in altitude and non arteritic ischemic optic neuropathy (NAION) (Boscher et al, Société Francaise d'Ophtalmologie and Retina Society, 2015 annual meetings).

Exogenous Recombinant human EPO (rhEPO) has been shown effective in humans for spinal cord injury (12), neurodegenerative and chronic kidney diseases (CKD) (reviewed in 13). Endogenous EPO is released physiologically in the circulation by the kidney and liver; it may be secreted in addition by all cells in response to hypoxic stress, and it is the prevailing pathway induced via genes up-regulation by the transcription factor Hypoxia Inducible Factor 1 alpha, among angiogenesis (VEGF pathway), vasomotor regulation (inducible NO synthase), antioxidation, and energy metabolism (14). EPO Receptor signaling induces cell proliferation, survival and differentiation (reviewed in 13), and targets multiple non hematopoietic pathways as well as the long-known effect on erythropoiesis (reviewed in 15). Of particular interest here, are its synergistic anti-inflammatory, neural antiapoptotic (16) pro-survival and pro-regenerative (17) actions upon hypoxic injury, that were long-suggested to be also indirect, via blockade of ET release by astrocytes, and assimilated to ET-A blockers action (18). Quite interestingly, endogenous EPO’s pleiotropic effects were long-summarized (back to 2002), as “mimicking hypoxic-preconditioning” by Dawson (19), a concept applied to the retina (20). EPO Receptors are present in all retinal cells and their rescue activation targets all retinal cells, i.e. retinal EC, neurons (photoreceptors (PR), ganglion (RGG) and bipolar cells), retinal pigment epithelium (RPE) osmotic function through restoration of the BRB, and glial cells (reviewed in 21), and the optic nerve (reviewed in 22). RhEPO has been tested experimentally in animal models of glaucoma, retinal ischemia-reperfusion (I/R) and light phototoxicity, via multiple routes (systemic, subconjunctival, retrobulbar and intravitreal injection (IVI) (reviewed in 23), and used successfully via IVI in human pilot studies, notably first in diabetic macular edema (24) (reviewed in 25 and 26). It failed to improve neuroprotection in association to corticosteroids in optic neuritis, likely for bias reasons (reviewed in 22). Of specific relation to the current case, it has been reported in NAION (27) (reviewed in 28) and traumatic ON injury (29 Rashad), and in one case of acute severe central RVO (CRVO) (Luscan and Roche, Société Francaise d’Ophtalmologie 2017 annual meeting). In addition EPO RPE gene therapy was recently suggested to prevent retinal degeneration induced by OS in a rodent model of dry Age Macular Degeneration (AMD) (30).

CASE REPORT PRESENTATION

This 54 years female patient was first visited on March 2019 4th, seeking for second opinion for ongoing vision deterioration OR on a daily basis, since around 3 weeks. Sub-central RVO (CRVO) OR had been diagnosed on February 27th; available SD-OCT macular volume was increased with epiretinal marked hyperreflectivity, one available Fluorescein angiography picture showed a non-filled superior CRVO, and a vast central ischemia involving the macular and paraoptic territories. Of note there was ON edema with a para-papillary hemorrage nasal to the disc on the available colour fundus picture.

At presentation on March 4, Best Corrected Visual Acuity (BCVA) was reduced at 20/100 OR (20/25 OS). The patient described periods of acutely excruciating retro-orbital pain in the OR. Intraocular pressure was normal, at 12 OR and 18 OS (pachymetry was at 490 microns in both eyes). The dilated fundus examination was similar to the previous color picture and did not disclose peripheral hemorrages recalling extended peripheral retinal ischemia. Humphrey Visual Field disclosed an altitudinal inferior scotoma and a peripheral inferior scotoma OR and was in the normal range OS, i.e. did not recall normal tension glaucoma OS (Fig. 1). There were no papillary drusen on the autofluorescence picture, ON volume was increased (11.77 mm3 OR versus 5.75 OS) on SD-OCT (Heidelberg Engineering®) OR, Retinal Nerve Fiber (RNFL) and RGC layers thicknesses were normal (Fig. 2). Marked epimacular hypereflectivity OR with foveolar depression inversion, moderately increased total volume and central foveolar thickness (CFT) (428 microns versus 328 OS), and a whitish aspect of the supero-temporal internal retinal layers recalling ischemic edema, were present (video 1). EDI CFT was incresead at 315 microns (versus 273 microns OS), with focal pachyvessels on the video mapping (video 1). OCT-Angiography disclosed focal perfusion defects in both the retinal and chorio-capillaris circulations (Fig. 3), and central alterations of the PR1 layer on en-face OCT(Fig. 4).

Altogether the clinical picture evoked a NAION with venous sub-occlusion, recalling Fraenkel’s et al early hypothesis of an ET interstitial diffusion-related venous vasoconstriction behind the lamina cribrosa (2), as much as a rupture of the BRB was present in the optic nerve area (hemorrage along the optic disc). Choroidal vascular drop-out was suggested by the severity and rapidity of the VF impairment (31). The extremely rapid development of a significant “epiretinal membrane”, that we interpreted as a reactive - and protective, in absence of cystoid macular edema (CME) - ET 2-induced astrocytic proliferation (reviewed in 32), was as an additional sign of severe ischemia.

The mention of the retro-orbital pain evoking a “ciliary angor”, the absence of any inflammatory syndrome and of the usual metabolic syndrome in the emergency blood test, oriented the etiology towards a FS. And indeed anamnesis collected many features of the FS, i.e. hypotension (“non dipper” profile with one symptomatic nocturnal episode of hypotension on the MAPA), migrains, hypersensitivity to cold, stress, noise, smells, and medicines, history of a spontaneously resolutive hydrops six months earlier, and of paroxystic episods of vertigo (which had driven a prior negative brain RMI investigation for Multiple Sclerosis, a frequent record among FS patients (33) and of paroxystic visual field alterations (7)(9), that were actually recorded several times along the follow-up.

The diagnosis of FS was eventually confirmed in the Ophthalmology Department in Basel University on April 10th, with elevated retinal venous pressure (20 to 25mmHg versus 10-15 OS) (4)(7)(9), reduced perfusion in the central retinal artery and veins on ocular Doppler (respectively 8.3 cm/second OR velocity versus 14.1 mmHg OS, and 3.1/second OR versus 5.9 cm OS), and impaired vasodilation upon flicker light-dependant shear stress on the Dynamic Vessel Analyser testing (7-9). In addition atherosclerotic plaques were absent on carotid Doppler.

On March 4th, the patient was at length informed about the FS, a possible off label rhEPO IVI, and a related written informed consent on the ratio risk-benefits was delivered.

By March 7th, she returned on an emergency basis because of vision worsening OR. VA was unchanged, intraocular pressure was at 13, but Visual Field showed a worsening of the central and inferior scotomas with a decreased foveolar threshold, from 33 to 29 decibels. SD-OCT showed a 10% increase in the CFT volume.

On the very same day, an off label rhEPO IVI OR (EPREX® 2000 units, 0,05 cc in a pre-filled syringe) was performed in the operating theater, i.e. the dose reported by Modarres et al (27), and twenty times inferior to the usual weekly intravenous dose for treatment of chronic anemia secondary to CKD. Intra venous acetazolamide (500 milligrams) was performed prior to the injection, to prevent any increase in intra-ocular pressure. The patient was discharged with a prescription of chlorydrate betaxolol (Betoptic® 0.5 %) two drops a day, and high dose daily magnesium supplementation (600 mgr).

Incidentally the patient developed bradycardia the day after, after altogether instillation of 4 drops of betaxolol only, that was replaced by acetazolamide drops, i.e. a typical hypersensitivity reaction to medications in the FS (7)(9).

Subjective vision improvement was recorded as early as D1 after injection. By March 18 th, eleven days post rhEPO IVI, BCVA was improved at 20/63, the altitudinal scotoma had resolved (Fig. 5), Posterior Vitreous Detachment had developed with a disturbing marked Weiss ring, optic disc swelling had decreased; vasculogenesis within the retinal plexi and some regression of PR1 alterations were visible on OCT-en face. Indeed by 11 days post EPO significant functional, neuronal and vascular rescue were observed, while the natural evolution had been seriously vision threatening.

However cystoid ME (CME) had developed (video 2). Indo Cyanin Green-Cine Video Angiography (ICG-CVA) OR, performed on March 23, i.e. 16 days after the rhEPO IVI, showed a persistent drop in ocular perfusion: ciliary and central retinal artery perfusion timings were dramatically delayed at respectively 21 and 25 seconds, central retinal vein perfusion initiated by 35 seconds, was pulsatile, and completed by 50 seconds only (video 3). Choroidal pachyveins matching the ones on SD-OCT video mapping were present in the temporal superior and inferior fields, and crossed the macula; capillary exclusion territories were present in the macula and around the optic disc.

By April 1, 23 days after the rhEPO injection, VA was unchanged, but CME and perfusion voids in the superficial deep capillary plexi and choriocapillaris were worsened, and optic disc swelling had recurred back to baseline, in a context of repeated episodes of systemic hypotension; and actually Nifepidin-Ratiopharm® oral drops (34), that had been delivered via a Temporary Use Authorization from the central Pharmacology Department in Assistance Publique Hopitaux de Paris, had had to be stopped because of hypersensitivity.

A second off label rhEPO IVI was performed in the same conditions on April 3, i.e. approximately one month after the first one.

Evolution was favourable as early as the day after EPO injection 2: VA was improved at 20/40, CME was reduced, and perfusion improved in the superficial retinal plexus as well as in the choriocapillaris. By week 4 after EPO injection 2, CME was much decreased, i.e. without anti VEGF injection. On august 19th, by week 18 after EPO 2, perfusion on ICG-CVA was greatly improved , with ciliary timing at 18 seconds, central retinal artery at 20 seconds and venous return from 23 to 36 seconds, still pulsatile. Capillary exclusion territories were visible in the macula and temporal to the macula after the capillary flood time that went on by 20.5 until 22.5 seconds (video 4); they were no longer persistent at intermediate and late timings.

Last complete follow-up was recorded on January 7, 2021, at 22 months from EPO injection 2. BCVA was at 20/40, ON volume had dropped at 7.46 mm3, a sequaelar superior deficit was present in the RNFL (Fig. 2) with some corresponding residual defects on the inferior para central Visual Field (Fig. 5), CFT was at 384 mm3 with an epimacular hyperreflectivity without ME, EDI CFT was dropped at 230 microns. Perfusion on ICG-CVA was not normalized, but even more improved, with ciliary timing at 15 seconds, central retinal artery at 16 seconds and venous return from 22 to 31 seconds, still pulsatile (video 5), indicating that VP was still above IOP. OCT-A showed persisting perfusion voids, especially at the optic disc and within the deep retinal capillary plexus. The latter were present at some degree in the OS as well (Fig. 6). Choriocapillaris and PR1 layer were dramatically improved.

Last recorded BCVA was at 20/32 by February 14, 2022, at 34 months from EPO 2. SD-OCT showed stable gliosis hypertrophy and mild alterations of the external layers (video 6).

Figure 1: Humphrey visual field at baseline on March 7th 2019, showing an altitudinal central scotoma, an inferior peripheral scotoma with a normal and symmetrical foveolar sensitivity threshold, and a normal visual field OS

Figure 2: Retinal Nerve Fiber (RNFL ) evolution from normal at baseline on March 2019 7th, to development of a superior sequellar deficit that remained stable on last follow-up.

Figure 3: OCT-Angiography at baseline on March 7th 2019, showing perfusion voids OR in the superior superficial retinal plexus and in the choriocapillaris.

Figure 4: OCT en face at baseline on March 7th 2019, showing PR1 layer deficits OR (artefacts in the superior half) compared to OS.

Figure 5: Humphrey visual field follow-ups : at follow-up 1 eleven days after rhEPO intra vitreal injection showing resolution of the altitudinal central scotoma and decrease of the inferior scotoma, and at last visual field follow-up on January 20th 2021, showing residual defects corresponding to the RNFL ones on Figure 2.

Figure 6: OCT Angiography performed on January 7th 2021, at 22 months from EPO injection 2, showing persisting perfusion voids, especially at the optic disc, and within the deep retinal capillary plexus, that were present at some degree in the OS as well.

Video 1 : SD-OCT video mapping OR at baseline on March 7th 2019, showing epiretinal hyperreflectivity and epiretinal membrane with foveolar depression inversion, ischemic edema in the internal and temporal to the disc superior retinal layers, and focal choroidal Haller pachyvessels with reduction in chorio-capillaris/Sattler layers.

Vedio: https://jmedcasereportsimages.org/articles/JCRMHS_1231_Vedio_1.mov

Video 2: SD-OCT video mapping OR at follow-up 1 eleven days after rhEPO intra vitreal injection on March 18th, showing epiretinal hyperreflectivity and epiretinal membrane with foveolar depression inversion, ischemic edema in the internal and temporal to the disc superior retinal layers, and development of central cystoid macular edema.

Vedio: https://jmedcasereportsimages.org/articles/JCRMHS_1231_Vedio_2.mov

Video 3 : Indo Cyanin Green-Cine Video Angiography OR, performed on March 23, i.e. 16 days after the rhEPO IVI, showing a persistent drop in ocular perfusion: ciliary and central retinal artery perfusion timings were dramatically delayed at respectively 21 and 25 seconds, central retinal vein perfusion initiated by 35 seconds, was pulsatile, and completed by 50 seconds only.

Vedio: https://jmedcasereportsimages.org/articles/JCRMHS_1231_Vedio_3.mov

Video 4 : Indo Cyanin Green-Cine Video Angiography OR, performed on August 19, i.e. by week 18 after EPO 2, showing greatly improved perfusion, with ciliary timing at 18 seconds, central retinal artery at 20 seconds and venous return from 23 to 36 seconds, still pulsatile. Capillary exclusion territories were visible in the macula and temporal to the macula after the capillary flood time that went on by 20.5 until 22.5 seconds.

Vedio: https://jmedcasereportsimages.org/articles/JCRMHS_1231_Vedio_4.mov

Video 5: Indo Cyanin Green-Cine Video Angiography OR, performed on January 7th, 2021, at 22 months from EPO injection 2: perfusion was not normalized, but even more improved, with ciliary timing at 15 seconds, central retinal artery at 16 seconds and venous return from 22 to 31 seconds, still pulsatile.

Vedio: https://jmedcasereportsimages.org/articles/JCRMHS_1231_Vedio_5.avi

Video 6 : SD-OCT video mapping at 34 months from EPO 2, showing stable gliosis hypertrophy and mild alterations of the external layers.

Vedio: https://jmedcasereportsimages.org/articles/JCRMHS_1231_Vedio_6.avi

DISCUSSION

What was striking in the initial clinical phenotype of CRVO was the contrast between the moderate venous dilation, and the intensity of ischemia, that were illustrating the pioneer hypothesis of Professor Flammer‘s team regarding the pivotal role of ET in VO (2), recently confirmed (3)(35), i.e. the local venous constriction backwards the lamina cribrosa, induced by diffusion of ET-1 within the vascular interstitium, in reaction to hypoxia. NAION was actually the primary and prevailing alteration, and ocular hypoperfusion was confirmed via ICG-CVA, as well as by the ocular Doppler performed in Basel. ICG-CVA confirmed the choroidal drop-out suggested by the severity of the VF impairment (31) and by OCT-A in the choriocapillaris. Venous pressure measurement, which instrumentation is now available (8), should become part of routine eye examination in case of RVO, as it is key to guide cases analysis and personalized therapeutical options.

Indeed, the endogenous EPO pathway is the dominant one activated by hypoxia and is synergetic with the VEGF pathway, and coherently it is expressed along to VEGF in the vitreous in human RVO (36). Diseases develop when the individual limiting stress threshold for efficient adaptative reactive capacity gets overwhelmed. In this case by Week 3 after symtoms onset, neuronal and vascular resilience mechanisms were no longer operative, but the BRB, compromised at the ON, was still maintained in the retina.

As mentioned in the introduction, the scientific rationale for the use of EPO was well demonstrated by that time, as well as the capacities of exogenous EPO to mimic endogenous EPO vasculogenesis, neurogenesis and synaptogenesis, restoration of the balance between ET-1 and NO. Improvement of chorioretinal blood flow was actually illustrated by the evolution of the choriocapillaris perfusion on repeated OCT-A and ICG-CVA. The anti-apoptotic effect of EPO (16) seems as much appropriate in case of RVO as the caspase-9 activation is possibly another overlooked co-factor (6).

All the conditions for translation into off label clinical use were present: severe vision loss with daily worsening and unlikely spontaneous favourable evolution, absence of toxicity in the human pilot studies, of contradictory comorbidities and co-medications, and of context of intraocular neovascularization that might be exacerbated by EPO (37).

Why didn’t we treat the onset of CME by March 18th, i.e. eleven days after EPO IVI 1, by anti-VEGF therapy, the “standard-of-care” in CME for RVO ?

In addition to the context of functional, neuronal and vascular improvements obviated by rhEPO IVI by that timing in the present case, actually anti VEGF therapy does not address the underlying causative pathology. Coherently, anti-VEGF IVI : 1) may not be efficient in improving vision in RVO, despite its efficiency in resolving/improving CME (usually requiring repeated injections), as shown in the Retain study (56% of eyes with resolved ME continued to loose vision)(quoted in (1) 2) eventually may be followed by serum ET-1 levels increase and VA reduction (in 25% of cases in a series of twenty eyes with BRVO) (38) and by increased areas of non perfusion in OCT-A (39). Rather did we perform a second hrEPO IVI, and actually we consider open the question whether the perfusion improvement, that was progressive, might have been accelerated/improved via repeated rhEPO IVI, on a three to four weeks basis.

The development of CME itself, involving a breakdown of the BRB, i.e. of part of the complex retinal armentorium resilience to hypoxia, was somewhat paradoxical in the context of improvement after the first EPO injection, as EPO restores the BRB (24), and as much as it was suggested that EPO inhibits glial osmotic swelling, one cause of ME, via VEGF induction (40). Possible explanations were: 1) the vascular hyperpermeability induced by the up-regulation of VEGF gene expression via EPO (41) 2) the ongoing causative disease, of chronic nature, that was obviated by the ICG-CVA and the Basel investigation, responsible for overwhelming the gliosis-dependant capacity of resilience to hypoxia 3) a combination of both. I/R seemed excluded: EPO precisely mimics hypoxic reconditioning as shown in over ten years publications, including in the retina (20), and as EPO therapy is part of the current strategy for stabilization of the endothelial glycocalix against I/R injury (42-43). An additional and not exclusive possible explanation was the potential antagonist action of EPO on GFAP astrocytes proliferation, as mentioned in the introduction (18), that might have counteracted the reactive protective hypertrophic gliosis, still fully operative prior to EPO injection, and that was eventually restored during the follow-up, where epiretinal hyperreflectivity without ME and ongoing chronic ischemia do coincide (Fig. 6 and video 6), as much as it is unlikely that EPO’s effect would exceed one month (cf infra). Inhibition of gliosis by EPO IVI might have been also part of the mechanism of rescue of RGG, compromised by gliosis in hypoxic conditions (44). Whatever the complex balance initially reached, then overwhelmed after EPO IVI 1, the challenge was rapidly overcome by the second EPO IVI without anti-VEGF injection, likely because the former was powerful enough to restore the threshold limit for resilience to hypoxia, that seemed no longer reached again during the relapse-free follow-up. Of note, this “epiretinal membrane “, which association to good vision is a proof of concept of its protective effect, must not be removed surgically, as it would suppress one of the mecanisms of resilience to hypoxia.

To our best knowledge, ICG-CVA was never reported in FS; it allows real time evaluation of the ocular perfusion and illustration of the universal rheological laws that control choroidal blood flow as well. Pachyveins recall a “reverse” veno-arteriolar reflex in the choroidal circulation, that is NO and autonomous nervous system-dependant, and that we suggested to be an adaptative choroidal microcirculation process to hypoxia (45). Their persistence during follow-up accounts for a persisting state of chronic ischemia.

The optimal timing for reperfusion via rhEPO in a non resolved issue:

in the case reported by Luscan and Roche, rhEPO IVI was performed on the very same day of disease onset, where it induced complete recovery from VA reduced at counting fingers at 1 meter, within 48 hours. This clinical human finding is on line with a recent rodent stroke study that established the timings for non lethal versus lethal ischemia of the neural and vascular lineages, and the optimized ones for beneficial reperfusion: the acute phase - from Day 1 where endothelial and neural cells are still preserved, to Day 7 where proliferation of pericytes and Progenitor Stem Cells are obtainable - and the chronic stage, up to Day 56, where vasculogenesis, neurogenesis and functional recovery are still possible, but with uncertain efficiency (46). In our particular case, PR rescue after rhEPO IVI 1 indicated that Week 3 was still timely. RhEPO IVI efficacy was shown to last between one (restoration of the BRB) and four weeks (antiapoptotic effect) in diabetic rats (24). The relapse after Week 3 post IVI 1 might indicate that it might be approximately the interval to be followed, should repeated injections be necessary.

The bilateral chronic perfusion defects on OCT-A at last follow-up indicate that both eyes remain in a condition of chronic ischemia and I/R, where endogenous EPO provides efficient ischemic pre-conditioning, but is potentially susceptible to be challenged during episodes of acute hypoxia that overwhelm the resilience threshold.

CONCLUSION

The present case advocates for individualized medicine with careful recording of the medical history, investigation of the systemic context, and exploiting of the available retinal multimodal imaging for accurate analytical interpretation of retinal diseases and their complex pathophysiology. The Flammer Syndrome is unfortunately overlooked in case of RVO; it should be suspected clinically in case of absence of the usual vascular and metabolic context, and in case of elevated RVP. RhEPO therapy is able to restore the beneficial endogenous EPO ischemic pre-conditioning in eyes submitted to challenging acute hypoxia episodes in addition to chronic ischemic stress, as in the Flammer Syndrome and fluctuating ocular blood flow, when it becomes compromised by the overwhelming of the hypoxic stress resilience threshold. The latter physiopathological explanation illuminates the cases of RVO where anti-VEGF therapy proved functionally inefficient, and/or worsened retinal ischemia. RhEPO therapy might be applied to other chronic ischemia and I/R conditions, as non neo-vascular Age Macular Degeneration (AMD), and actually EPO was listed in 2020 among the nineteen promising molecules in AMD in a pooling of four thousands (47).

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florencemtrash · 10 months ago

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The Shadowsinger & The Inkbird: Chapter Eleven

Azriel x Day Court Librarian Reader

Summary: Y/n's clairvoyance is a gift from the Mother, but it feels more like a curse. With the power to gain knowledge through touch alone, Y/n holes herself up in The Alcove and hopes her powers and parentage will remain a secret. But things will change after the Summer Solstice ball and a chance encounter with a certain Shadowsinger.

Warnings: None. Gwyn and Y/n bond over books. Azriel and Y/n get even closer — this had me kicking my feet and screaming internally and externally

The Shadowsinger & The Inkbird: Masterlist

Masterlist of Masterlists

Rhysand’s training sessions always started with him sliding over ten objects: a book, a piece of jewelry, an article of clothing — anything he could find with meaning for you to discern.

“This one is Mor’s.” You held the red satin box in your hands. Two months ago you would have only been able to tell him who it belonged to. Maybe nothing at all. The meaning held by the object was weak. The jewelry too new. Unworn. But now you could harness your power with more precision, like you’d finally been handed an image of the puzzle you were trying to complete so you knew what to look for. “You bought it two months ago at Cizero’s as a Winter Solstice gift.”

“And what is it exactly?”

The box was still closed.

You pushed your power forward, imagining light slipping in through the seam of the box. An image flashed in your mind. It was blurry, but held onto its form long enough for you to make it out.

“Drop earrings. Rubies,” you said with a straight back before dropping the box into Rhysand’s open palm.

He smirked and clicked it open. Gold banded rubies hung from the backing like bloody tears, each drop separated by a diamond that flashed brighter than the stars in the ever darkening sky.

You dared to smile, staring at the jewelry with a level of satisfaction you hadn’t felt since being handed top marks as an apprentice.

“Very nicely done.”

The box disappeared back into his desk beside a glimmering gemstone the size of your fist wrapped in tissue paper.

It’s probably for Amren. You thought to yourself. Azriel told you she loved shiny things and hoarded her treasures like a crow. Hence why she’d yet to return from Summer with Varian.

You moved on to the next portion of your exercises. With a feather light touch, Rhysand laid his hands on your palms, your wrists, your forearm, your shoulders. He moved up and down your body, waiting a minute for you to control yourself before touching the next flash of exposed skin. It was still difficult to completely contain your power, but you were getting better at moving it around your body. When he reached for your hands, you slid the magic up to your chest. When he reached for your knees, it moved down to your ankles. It was a delicate dance, like the curling of ocean water away from the shore or the splitting of a river around a stone.

You did what you could to experience the touches with a clinical detachment and Rhysand did as well. He was careful. He stopped the moment you let out a gasp of surprise at the feeling of warm skin pressed against your own and there wasn’t an ounce of judgement written in his beautiful features when you trembled beneath his touch.

“Take your time,” he said encouragingly.

For him, touch was a necessary part of life. He always had an arm slung over Cassian’s shoulders or wrapped around Feyre’s waist. He fell asleep with his mate pressed against him and he walked around the River House with Nyx on his shoulders and Velaria curled up in his arms. But there were also mornings when he’d wake up in a cold sweat, the feeling of Amarantha’s red-tipped nails dragging down his chest like she wanted to take more from him than just his body. Those were the days Feyre knew to give him his space.

“Take all the time that you need.”

Rhys stepped away. You steadied your breath and took time to record your progress in the journal you kept close by. Although there was no true way to quantify your learning, your Day Court training never left you and you wrote down what little could be put into words — for posterity’s sake. Then maybe the next Clairvoyant the Mother willed into existence would have an easier time navigating this than you.

Gwyn found you squirreled away in your usual reading room, back bowed over a flurry of books and note pages like a reed in the wind. You reached for the mug on the desk only to find it disappointingly empty. Unlike the River House, the Library did not fuel your caffeine addiction with reckless abandon.

She floated over, abandoning the cart of books she’d been tasked with returning that night. Her legs were throbbing from the split squats Cassian had coached her through that evening, and she was desperate for a break.

“Some light reading, I see?” she teased, sinking into the seat across from you.

You looked up, eyes red-rimmed and swollen. It took a few moments for Gwyn’s shape to come into focus.

“What?” The word slurred coming out of your mouth.

She tapped the ever growing pile of papers beside you. Your manuscript: 120 hand-written pages and counting. When the book became too frustrating to handle, you abandoned it in exchange for another productive task. Even if the 120 pages you’d reproduced were utter garbage.

You groaned, forehead slamming against the wood with a clatter. Thoughts of white blood cells, lymphatic vessels, and innate and acquired immunity knotted in your brain like the world’s worst game of cat’s cradle.

Gwyn would have found it amusing if she didn’t know just how much time you spent within the mountain. You’d effectively been adopted by the priestesses. Lurking here and there like a cat coming in from the cold. And you were just as disapproving as a stray. Gwyn would often catch you among the stacks, mumbling about the disorganization and how you couldn’t work in such paltry conditions.

“Cauldron boil me, I’m sorry for asking.” Gwyn raised her hands in surrender.

You let out a great, heaving sigh. “It’s not you.”

“Oh I know it’s not me. You look like you’ve been dragged through a gutter.”

You blinked wearily at the lovely priestess.

“A very clean, well-managed gutter.” She grinned. Her skin shone, reflecting the pale, fuzzy moonlight that filtered through the window above and doused the library in a silver sheen.

“Thank you, Gwyn.”

“Anytime.” She drummed her nails against the table, the beat of it almost sending you to sleep. “How long have you been here today?” she asked with concern.

“I don’t know. What time is it?”

“After midnight.”

“Oh.”

“How long?” Gwyn repeated and you dragged a hand down your face.

“Seven hours? Give or take?” Your stomach growled.

“Oh for fuck’s sake.”

Gwyn grabbed you by the end of your robes, tugging you up several floors and down an unfamiliar hallway until you stopped in front of a teal-blue tapestry. Selkies, sirens, and water nymphs dove in and out of rippling waters highlighted by iridescent beads. She flung it to the side and pressed her hand against the bare stone. The slab sank into the wall and then slid open to reveal a cream-colored room adorned with bundles of babies' breath.

“Sit,” she commanded, pointing to the neatly made bed. You swayed dangerously on your feet.

“I’m really fine. I didn’t mean to bother you.”

“Sit. Down.” She cut you with a lethal gaze Nesta would be proud of.

You snapped your mouth shut, shuffled across the carpeted floor, and sank into the queen-sized bed. You played with the ties of your robe wrapping them around your finger, then unwrapping them, then wrapping them again.

King Tiberion, third of the Nachmanian line, born Aschieron Cambria Nostrus Tiberion Dalgna to Effel Taul and foreign-born…

Found dead at a young three-hundred-and-ninety-two years of age at the hands of her brother. Spell cleaver or not, Ingrid…

Something like a lock and a key. Magic that’s perfectly complementary might be afforded the unique ability to seal… and break… gods I’m tired…

There have only been seven recorded Shadowsingers in history: Lovania Vallant born 895 in the age of Alders (see ref. 18992HBG Carstairs), Gherald Dashiv born 1459 in the age of —

Gwyn snapped her fingers in front of you, pulling your mind out of the hurricane of thoughts. You were a strange creature. You spoke little, moved about the Library as quiet as a mouse, and you had an interesting habit of running your fingers along every book on the shelf. Back and forth, back and forth you’d run along before jerking to a stop like one of the books had caught you at the end of a fishing lure.

“Are you ok?”

“I’m fine,” you repeated.

“You’re a terrible liar.”

“Some would say that’s a good thing. It would make me incredibly trustworthy, at least when it comes to responding to things. I’d be terrible at keeping secrets, unless I was very careful about how I went about things. You know how it is. With the things.”

Gwyn huffed with silent laughter and opened one of the cabinets in her small, makeshift kitchen. “Eat.” She commanded again and you were too slow to catch the sleeve of biscuits she tossed in your direction. It bounced off your forehead and landed in your lap. “I’ll be right back with something more substantial.”

The door shut with a puff of air and you were left to chew on the chocolate and orange biscuits in silence.

Gwyn’s room faced the city and you saw the lamplights burning through the windows that had been cut into the mountain rock, mimicking the stars that twinkled overhead like salt poured onto black glass.

Cream satin sheets caught the moonlight until it glowed and you had the sudden urge to tip back and fall into oblivion. You could work for a long while, so long as you didn’t sit still long enough for the exhaustion to catch up to you — which you were doing now.

You shoved another biscuit in your mouth, now almost halfway through the sleeve. It helped settle the hollowness in your stomach so you could pick yourself up and move over to the bookshelf.

Bodice ripper, bodice ripper, murder mystery, bodice ripper, romantic comedy, found family adventure, spy thriller, bod—

Your face went red. Damn.

The priestess chose that moment to return to her room carrying a tray laden with bread, orange slices, and a thick mushroom stew leftover from dinner. She froze, pale cheeks turning a dusty rose as you silently pushed the book back onto the shelf.

“Dragon-born? Really?” You shoved a burning spoonful of stew in your mouth and drowned the stale crust of bread, waiting for it to get sufficiently soggy enough you could chew it.

Gwyn groaned and buried her face in her pillows. “It was a phase.”

“Must have been a very long phase. You have the whole series and I know it took her thirty years to write them all.”

Her head shot up. “How do you know?”

“I read the first book.”

You sat up straighter, back pressed up against the closet that housed her daily robes, ceremonial garb, training gear, and Valkyrie armour.

“So how can you judge me?!”

“It makes no anatomical sense, Gwyn!” You threw your hands up in the air. “She’s four feet shorter than him. He’d sooner tear her in half before giving her any pleasure, and I’m not talking about his claws.”

The priestess scoffed. “Have some imagination, Y/n.”

You huffed and pulled out a notebook from your ample pockets. You both spent the next thirty minutes going through hastily drawn sketches that would have disappointed Feyre to no end testing out your imaginative capabilities. Gwyn couldn’t stop smiling at you as you moved your hands through the air with animated fervor. Half of what you said didn’t make sense, but she would blame it on your sleep deprivation.

You had Gwyn in stitches. The female hung off the bed, red-brown hair brushing the ground as she gasped for breath. You looked like you were sitting on the ceiling, black robes pooled around your knees like shadows.

That sobered Gwyn up a bit. It was a real shame she liked you as much as she did. It made it harder for her to stay mad at Azriel.

And as if you read her mind, you asked, “Why don’t you come around to the River House?”

“What?” She wasn’t laughing anymore.

“Why don’t you come to the River House?” You asked again. “You’re close friends with Nesta. You’re part of the Inner Circle. You have a guest room there, but I haven’t seen you at the house.”

“Do you even spend enough time at the River House to know?”

“Yes.”

Gwyn sighed and straightened up, folding her legs neatly beneath her on the bed. “Some… Some things happened a couple years ago. I won’t bore you with the details and I don’t know if I even have the right to tell you everything, but it’s colored the way the Inner Circle works now.”

“The details are the most important part,” you murmured, “I wish I had more details. Then maybe I wouldn’t feel like such a stranger in that house.”

“You’re not a stranger,” Gwyn reassured you. “Is that why you spend so much time here?” she asked with genuine curiosity.

“Yes and no. It feels closer to home here. Even if your lack of organization has made my job ten times more difficult. I don’t see why you haven’t adopted any kind of classification system. It’s a small library. It would be very easy to implement.” You sighed and rubbed your eyes. Gods, you were tired. The feeling came and went in waves. “I shouldn’t complain though, everyone has been incredibly kind and welcoming. Especially Azriel.”

You wrapped your arms around yourself, fingers fluttering against your shoulders. You tucked your chin into your elbows and tried not to think about that glorious night of sleep with only Azriel and his shadows. Waking up with his chest rising and falling on the floor beside you.

You were falling for him and you knew it. Gods did you know it. Or maybe you could convince yourself you weren’t falling yet, but it was a steady march to the cliff’s edge and you weren’t stopping anytime soon.

Gwyn felt her heart stutter. “Oh? He’s usually so… quiet and… reserved.”

You thought about it for a long while.

“I don’t think he’s nearly as quiet as everyone believes him to be,” you said thoughtfully, “I think he just speaks in his own way.”

You were right about Godswood and The Gallows.

The letter arrived on your desk early in the morning.

The Bookkeeper, Taunum Hyst, was found trying to burn books in the western greenwoods along with some texts from Argot’s. He fought back against the guards sent to retrieve him, but he didn’t know what he was doing. Even now he’s confused and adamant that the last three weeks have been a blur. There’s a daemati at work here. Someone other than Henna. Rhysand knows, if he hasn’t already told you.

I’ve sent a translated folktale in old Bauldish and Common, and another in Demnyon along with the others you asked for. They might be worth looking into to help with the book. I hope you’re enjoying your stay at the Night Court. Happy hunting and stay safe.

~ Helion

You were right.

You dropped the letter, hands coming up to your mouth as you took in a deep, shaky breath. You knew Taunum Hyst. You could picture his salt-grey braids and coal-black skin. He’d helped perform the funeral rites for your mother. Hell he’d managed to make you laugh that terrible day.

Your stomach turned. If there truly was another daemati left in the Day Court that could help explain the killings. Either the Librarians could have died trying to keep the knowledge in their minds safe, or the daemati had made them kill themselves before moving onto their next victim. You didn’t know which was more tragic.

The clock rang eleven bells and you hastily folded up the paper, dropping it into the box along with the rest of your father’s letters.

“I think this might be the first time you’ve ever been late,” Rhysand said with an amused smirk. He leaned against the doorway to his office, ankles crossed over one another. Did that male ever stand normally?

“It is the first time.”

“Of course you would know that.”

You smirked, pushing open the door to find—

“Azriel?”

The Shadowsinger stood with his hands neatly folded behind his back. “Y/n?”

“Cassian!” The Lord of Bloodshed leapt in front of his brother, arms spread wide. “I’m also here. Nesta couldn’t make it with Valkyrie training.”

Feyre rolled her eyes with affection. She reached for Rhysand’s hand without thinking and he accepted with barely a glance. They were two magnets, always pulled towards one another in space.

“What’s going on?” You glanced back and forth between them all. It had always been just you and Rhysand during these lessons.

“I thought it would be good to start practicing with other people when it comes to physical touch,” Rhysand explained. Azriel’s nostrils flared. “You’re getting comfortable with me, which I’m happy about. But I want you to get comfortable with everyone else too.”

You told me you wanted another debrief about the Mortal Lands. Azriel was loath to admit that just the thought of touching your hand was making his heart race like a schoolboy.

And I do. Rhysand said rather smugly, as if he already knew Azriel was freaking out inside. But I also know you wouldn’t have agreed to this if I asked you ahead of time. It’s amusing to see you like this, brother. Have you forgotten how to touch a female? His violet eyes glittered with mischief.

Azriel swallowed, eyes trained on you as you mulled over Rhysand’s comment and nodded. You wanted to be comfortable too. Comfortable in your body. Comfortable with other people touching you.

You thought of what it might feel like to have Azriel’s hand tucked beneath your chin, not just his shadows, and shivered.

Azriel nearly choked when you started undoing the ties of your robes. The gold embroidered fabric slipped off your shoulders in a soft hush that had Azriel going rigid. You wore traditional Night Court fashion beneath your Librarian robes — a tight black shirt revealed the gentle curves of your arms, the cut of your collarbones against your chest, the thin band of flesh around your stomach; a breezy skirt with slits cut into the sides that revealed flashes of your thighs with every movement you made.

Feyre, Rhysand, and Cassian all shared looks, nearly bursting out laughing at the way Azriel’s shadows were in flight around him. A swarm of bees buzzing and murmuring about how beautiful you looked.

Azriel had seen many fae in his time in various states of undress. He’d seen males and females in the Court of Nightmares parade about in scraps of silk and lace. He’d taken countless lovers to bed. Bodies were something he knew well. Something he knew intimately. But he had never felt so flustered as he did looking at you like this. He thought his heart might just burst in his chest.

Cassian elbowed Azriel in the ribs when you weren’t looking and one of Azriel’s shadows looped around his ponytail and pulled.

“Ow.” Cassian rubbed the back of his head with a grin. “Rude.”

You felt rather ridiculous standing in the center of the room with your arms and legs stretched out to the side.

“Right arm,” Rhysand called out.

Cassian bounced back and forth on the balls of his feet, fists held loose by his sides with the lightness of a male a quarter of his size.

You squinted. Is he… is he about to punch me?

Cassian read the alarm on your face and grinned, hitting you with a tap gentler than rainfall.

You snorted, but felt nothing. Perfect.

You had to be grateful for Cassian’s light-heartedness. He had the worry melting off your shoulders. With every limb that Rhys called out, Cassian would do a little dance before punching you or kicking you. At one point he even faked a blow to your face, spinning up to you before leaping into the air and shooting out his right leg. You didn’t flinch as his boot swung an inch away from your face. You could smell the rubber soles of his boots.

“You missed,” you teased.

Cassian pouted, turning around to walk back to the wall now that he was finished with his piece. Azriel looked ready to tear his head off his body.

You’re lucky you missed. Azriel’s eyes screamed across the room. You’d be a dead man if you hurt her.

Cassian winked and blew him a kiss.

Feyre was next. You practiced brushing against her like you would do in a crowded street complete with the obligatory fumbling of apologies.

“Oh good heavens.” Feyre fanned her face like the old, upper-class women in her village used to do and laid on that sickly sweet accent they all had. “I’m so dreadfully sorry.” — They never were.

She shook your hand and touched your shoulders and looped her arm around your waist. That was the part that had you worried. You slid your power away from every inch of your skin, wrapped it up like a secret, and held it deepin your chest.

“Good.” Rhysand smiled and Cassian punched the air.

You breathed deeply and gave a small bow like you’d just finished a performance. But there was still one person you were meant to touch today, and they made you the most nervous of all.

Azriel stepped forward, a picture of calm. Inside, he was raging like a storm. He kept his hands firmly grasped behind his back, wings pressed so tightly he felt his shoulders start to ache.

You took a step forward as well, tilting your head back to look at him. You felt the grip on your power falter when he held out his hand palm up like he was asking you for a dance. Months ago at the Summer Solstice ball you’d been approached by a number of males hoping for a song with their hands at your waist and at your shoulder. The prospect of that kind of touch had terrified you then, and it still terrified you now but for different reasons. Because this time, you wanted it.

You wanted him.

You gently slid your hand into his, feeling the scars roll beneath your soft skin like the mountains that surrounded Velaris. Your breath caught in your throat, but before Azriel could rip his hand away you held on and squeezed reassuringly.

You’d read hundreds, if not thousands, of romance novels in your time. You’d consumed them with a ravenous hunger, surviving on them when real touch felt like a hopeless dream and the loneliness became too much to bear. And in nearly every single one of them, the first touch between lovers was described as an explosion of color. A dangerous shaking of the world down to its foundations. A cataclysmic event.

But you were surprised to find that they were wrong. They were all wrong. Azriel wasn’t destroying anything. He was mending.

It felt like a re-centering. The shifting of a leaning tower so it stood upright again.

A blissful silence.

Azriel cradled your hand in his, thumbs smoothing over your knuckles. He couldn’t help what he did next, couldn’t have stopped himself even if Helion stood at his back with murder in his eyes.

He leaned down and pressed a kiss to the top of your hand with such reverence, such tenderness, that you swore your heart was glowing in your chest.

“Why don’t you try a hug, Y/n?” Rhysand suggested when Azriel had straightened. “If you want.”

You looked down at your feet where shadows swarmed, and then up at Azriel.

“What do you say, Y/n?” Azriel murmured softly. His words were for you and you only. “Where would you have me touch you?” His hazel eyes caught the light before scattering into a thousand brilliant colors.

Wordlessly you ran your fingers down his arms, tracing the shape of the muscle beneath the leather. You held his hands and gently led them up to your waist, gasping when he made contact. His warm fingers brushed the exposed skin of your waist before sliding around to your back.

You balanced on the tips of your toes, looping your arms around his neck before resting your face in the hollow between his neck and shoulder. He smelled like leather and the mountains. Wind and rain and nightfall coalescing into something so uniquely him you could pick him out in a room of thousands with your eyes closed.

It started out as a loose, misshapen thing, your hands and his arms searching for the right grip to hold your bodies together. But once you found it, you were lost.

Azriel wrapped his arms around your back and waist, hands splayed out like he was absorbing you into him. And you were no better. You buried your face in his neck, lips pressed up against the curve of his throat so you could feel the rhythmic rush of blood through his veins.

He refused to be the first to let go. The roof could cave in. The floor could drop out from beneath your feet. He would not let you go.

Your tears started out slow, coupled by ragged, shallow breaths.

“I’ve got you, Y/n,” Azriel whispered. “I’ve got you.”

How long had it been since you’d been held like this? A hundred years? Two hundred? You thought you’d learned to live without it, but now that it was yours you didn’t think you’d ever, ever be able to give it up. You were at the cliff’s edge now and without an ounce of hesitation you flung yourself over and into the abyss.

With Azriel, controlling your powers didn’t seem like such a difficult thing. Later that evening when you lay in bed staring up at the ceiling, you realized you hadn’t been thinking of control at all.

<- Previous Chapter Next Chapter ->

______________

Author's Note:

Y'all... THEY FINALLY TOUCHED EACH OTHER! And not only that, BUT HE KISSED HER HAND!!! And! They fucking HUGGED!!!!

#azriel x reader #azriel x reader slow burn #azriel x y/n #azriel x you #the shadowsinger and the inkbird

844 notes · View notes

xzaddyzanakinx · 9 months ago

Text

Not That Kind of Guy

Part Four: Stalker!Anakin Skywalker × femme reader series

Warnings: stalking, weirdo behavior, psychotic/delusional behavior, possessive/protective, sexism/misogyny, one-sided relationship, sexual content, pervy behavior, male masturbation, panty kink, sex daydreams [eventual warning for smut; be sure to pay attention to future warnings in the series]

Info: Anakin is doing his very best, he just loves you and wants you to be comfy around him. Just let him worm his way into your heart babe [diary entries from Ani] extremely not proofread. I’m illiterate so apologies in advance MDNI 18+

Diary Entry: July 8th

Mr. Nelson’s funeral was today, it really was a beautiful ceremony as I look back on it. Even more so when my inner self smears the background enough to bring you to the front of the mental image.

You’d spoken to the man a handful of times, but I didn’t expect you to come. When I saw you accept the invite to the event on Facebook I thought surely it was a mistake. That was until you messaged Luke and asked him to accompany you, funerals make you nervous, but feeling obligated to do something and avoiding it makes you more nervous.

So your moral support was happy to attend and fight off dear old Alan’s corpse should he rise from the casket and set his sights on you.

And I though I had irrational fears, geez babydoll, how old were you when you watched Night of The Living Dead for the first time? If I had to guess it was too young. It’s alright though I get it, you know what movie traumatized me? The Mummy. Heebied my fucking Jeebies so bad I avoided the beach on family vacations.

You’re telling me there’s not a sarcophagus under all that sand? There’s at least one under there and you can’t convince me otherwise.

Solid ground for me only, please and thank you.

🖤🖤🖤🖤🖤🖤

I had a thought that I initially considered to be a sweet reminder of my dear friend Alan. His obituary was in the newspaper and I happened to swipe one from the guest book table at the viewing as well. Have you ever scrapbooked before? I bet you’ve at least tried it.

Well I thought it would be nice to make him a page in my journal. A little celebration of life for the man who gave me an opportunity to grow and nurture my love for you.

Then I realized mid-glue stick on the newspaper clipping that the idea was something that a clinically insane person would do.

I’m not that guy. That guy’s not me.

But the glue was already on there and it felt wrong to toss Alan’s wrinkly old face into the trash so I pasted him into my journal anyway.

Crazy people don’t know that they’re crazy. I’m well aware that little idea was less than tasteful, just felt like I should mention that.

Date:

July 28th

Anakin Skywalker hadn’t been this happy since… ever. The previous record being his discovery of you, was now toppled into second place and overshadowed by ‘Move In Day’.

He could hardly contain himself. It was a dopamine high that he would ride out until he’d drained every last drop.

The movers lugged in box after box, furniture and books, until finally they dropped off the last load and thanked Anakin for the business. He eagerly shook their hand and shoved them out. He had preparations to make.

He set up his Tv, screen mirroring the live feed of the apartment building entrance to the big screen so that he could easily keep an eye out for you while he unpacked his kitchen.

He’d planned your ‘meet-cute’ meticulously, looking to your bookshelf and streaming services to gather intel on your ideal scenario. You were an odd bird, but he liked that about you. It’s part of your charm, it’s part of the challenge. You’re not as predictable in your tastes and interests as others can be.

Anakin formulated the interaction step by step, frame by frame in the storyboard of his imagination until he had the perfect scene. His box office hit that he’d replay over and over again until the next time he stood face to face with you.

It took quite some time and a load of practice. Discarded dialogue, awkward movements that made him feel stiff and less than human when he practiced them in the mirror. Endless options of clothes, shoes, and hair.

Should he get a new piercing? He wanted to. So he did, he knew you’d like it.

It’d match the one he already had on the opposite nostril. It made him feel more complete to add something so permanent to his body, he wished he could do something similar with you. He wanted you to be permanent, so maybe it’s his subconscious’s way of telling him that this was going in the right direction.

He was on the right path. His journey of life alone was coming to a close and a new trail would reveal itself. No more rocky, unsteady tread. No more sharp turns and blind spots, no more impossible inclines.

Scraped knees and bloodied hands would be distant memories. Maybe even distant enough that he could toss them into The Pit.

He would have no need for anger or sorrow anymore.

How could he feel anything but the warm embrace of love as he strolled down the flowered path ahead with you?

Who knew that you could position one box in 83 different ways and hate every single one of them? Anakin was so thankful there weren’t any actual surveillance cameras in the apartment building. It’d be really difficult to explain why he was in the hallway for an hour with his hands on his hips, scooting a box of books a centimeter or two at a time. Turning it sideways and then making sure the book on top was perfectly positioned and would effectively fall to the ground to catch your attention.

He checked his watch nonstop, stared at his Tv screen, willing you to just hurry the fuck up before he vomited from anxiety. He’d waited months for this. If he fucked it up now he’d… well he’d probably keel over on the spot.

Which would promptly traumatize you and not even his ghost would be able to peacefully haunt you. It’s hard to peacefully haunt someone if they watched you die, or at least Anakin assumed it would be difficult. He wasn’t willing to test that theory though.

So, he puffed up his chest and walked back into his apartment and rehearsed the upcoming conversation a few more times. He needed, desperately needed to ensure his facial expressions conveyed what he wanted.

Soft, trustworthy, dependable, safe, caring.

He practiced softening his eyes, knowing sometimes he stared alittle too hard. He worked on his facial fidget; chewing on the inside of his cheek was a quick tell of his nervousness. He didn’t want to be perceived as nervous, he wanted to be confident and sure of himself so that you would be confident in your soon to blossom affection for him.

His eyebrows, that’s a hard one, but he’d meticulously watched bar goers trying to flirt. The successful ones he learned, sometimes use their eyebrows in place of questions or words. A difficult concept, but one he studied until he mastered it.

Now, the other facial expressions and mannerisms… he gathered that information from your watch lists on your streaming services. For the visible examples at least, but your books were just as helpful in describing how he should approach you, speak to you, and simply exist near you.

He hadn’t realized these things were this important until now. Standing and posture was surprisingly very, very important to women. As well as hand movements and subtle glances and minuscule changes of expression.

You were worth the time and effort it took to learn all of it. He’d read and research and practice until he couldn’t stand to look at himself in the mirror any longer. He was determined to make sure you were happy with the results.

He was startled by a loud ping, someone had entered to building and holy shit it was you.

Anakin shook out his hands frantically, remembering the breathing techniques he’d learned as a child, he grounded himself quickly.

It’s okay.

‘She’s gonna love you. She’ll warm up to you quickly, you know everything you need to know about her to make her comfortable and loved.’

‘There’s no way she won’t fall head over heels.’

He smoothed out his band-tee and ran his hands through his hair quickly and headed to his door that was propped open slightly. A few boxes sat in the hall, including the most important one, the one instrumental to his plan.

The apartment hallway was ridiculously tiny, which worked in his favor in this situation.

He heard you come up the stairs, counted your steps until he knew you were almost at the door, 17 and a half steps. Then he swung open the door and bent down to grab one of the boxes.

As expected, he startled you and you dropped your keys. You always wore your backpack on one shoulder, one strap. So when you quickly went to scoop up your keys, your bag swung out of place and toppled a few books from one of the boxes.

Perfect. Absolutely perfect.

Anakin could gloat to himself about his magnificent setup later, right now he needed to woo you with his sweet words.

“Oh, sweetheart I’m sorry.” He said softly, coming over to offer you a hand up.

“It’s okay, my bad.” You laughed, taking his hand.

He managed to keep calm and collected despite his insides boiling him alive at the willing skin contact.

“No, not at all. It’s my fault for startling you like that.” He chuckled, squeezing your upper arm and using his hand already in yours to give you a small handshake. Smooth.

“I’m Anakin.” He said with a bashful smile, dropping your hand and reveling in the lingering warmth your palm left on his.

You introduced yourself in return, gesturing to his apartment door.

“So I take it that you’re my new neighbor huh?” You said, making small talk as you crouched down to pick up the books you’d knocked over.

“No I’m just a one man moving crew.” He grinned.

“Very funny.” You laughed, standing up as you looked through the titles. “Hmm, you’ve got good taste.”

“You think so?” He asked, remembering to make his eyebrows swoop up toward the middle of his forehead to give a quizzical look.

“Oh yeah, this is one of my favorites.” You said, showing him the cover of The Silmarillion by Tolkien.

“Not many people actually read that one, I’m impressed.” He smiled.

“Impressed? Yeah well I’m jealous.” You laughed.

“What?” He chuckled, holding his hands out to take the other books from you.

“This is a really nice edition, it’s similar to mine. I recently lost it.” You sighed. “I think I must’ve left it the park or maybe it fell out of my bag or something.”

“Ah, that sucks… well, I mean I’ve read that one a few times now. It’s been well loved.” He said tipping the books in his arms toward the one you were holding. “Why don’t you keep it?”

He shrugged, acting nonchalant as though this didn’t mean the entire world to him and if you said no he’d sob about it later.

“You’re serious?” You asked in surprise, he was offering you a 50$ special edition book and you’d barely known him for a minute.

“Yeah, ‘course sweetheart.” He said with a cute, crooked smile. “Think of it as a… reverse house warming gift.” He chuckled.

“Thank you, I- this means a lot to me.” You said, grinning widely. “That’s real sweet of you Anakin. I owe you one.”

“No worries.” He chuckled, “I’m sure we’ll find a way to make it even sweetheart.” His gaze flickered quickly from your eyes to your lips, and he turned to go back into his apartment after giving you an almost-missed wink.

You stepped inside your home, and went straight to the bookshelf to put your new-to-you book where it belonged. After the fact you stood there and buffered, just staring at it.

‘There’s no way, this guy has to be too good to be true.’

But he seemed… so genuine. He didn’t ogle you, he didn’t make you feel weird or like he just felt obligated to speak to you.

He seemed to actually, really be a good guy.

Rare. Few and far of those exist in this day and age. It’s uncommon to meet someone who would do something, even as simple as giving you a used book, without expecting anything in return.

But he didn’t seem to expect anything. He didn’t seem to even expect a thank you, it was like he’d already decided he would give it to you before he even offered.

What are the odds that a hot, tattooed and pierced man moves in next door and gifts you an expensive book that just so happens to be an even better replacement for the one that you just lost? That couldn’t happen twice even if you tried to make it happen again.

What kind of second dimension did you step into? The land of dreamy men?

Diary Entry: July 28th

It’s late. But I have to write to you, it can’t wait til tomorrow.

Everything went more perfectly than I could’ve imagined. Thank you so much for being you sweet girl. It made my job of curating the scenery so much easier, you clumsy little thing. I am sorry for having to spook you though, but it worked didn’t it?

Research pays off. Always.

And of course there’s the issue of your book, I hated to see your frustration and your mad scowl when you realized it was missing from your backpack. I really did.

But I’d do it every goddamn day if I knew I’d get the same reaction out of you from giving you that new copy.

Oh god you’re… you’re beautiful. You’re so beautiful. You look angelic when you sleep but you look like competition for Aphrodite when you smile at me.

You smiled, grinned. You smiled all the way up to the corners of your bright and beautiful eyes. For me.

You even laughed for me.

It was so sweet I could taste it. The honey of your voice, I could fucking bathe in it. Just the sound of you speaking, knowing you were speaking to me. Really speaking to me.

In the flesh.

It’s intoxicating. It’s emboldening, it’s dangerous. I’ve never been more worked up in my life. I’m torn all to pieces from at two minute and 6 second conversation.

I think I’ll have to fucking recover from this like a damn hangover.

But what has me so drunk you might ask? Was it your laugh at my stupid jokes? Was it your perfect smile, your radiant glow, your soulful eyes? The softness of your skin or you willingness to let me touch you?

No baby. It’s how you said my name.

I wish I could’ve stayed longer, I wish I could’ve spoken to you more. But it’s so hard to concentrate when my dick is leaking precum down my leg at a rate that should probably be concerning.

The minute you closed that door I shoved those boxes into my apartment and locked the door. Took my elated ass straight to the couch and watched you in your living room, admiring your gift from me while I fucked my fist with a pair of your dirty panties in my mouth.

I couldn’t have your honeyed lips soothing my angry red cock just yet, but I sure as hell could imagine licking your gorgeous little cunt while I tasted you.

I tugged my balls and pumped my cock for over half an hour until I was a fucking mess for you in my new living room’s floor. The cool hardwood letting the heat from my flushed skin seep away from me as I came back down to earth.

I made myself dizzy. Didn’t give myself a break, didn’t slow down, just stroked my cock like the desperate little manwhore that I am for you. The only thing missing was you being there to watch me fall apart.

I think you’d like that wouldn’t you? Watching a man like me get on his knees and beg for you?

Diary Entry: July 29th

I’ve replayed that moment in my head for hours on end. The beginning always stays the same, but the ending… that’s been subject to many changes. It started off simple, we’d chat alittle longer, I’d ask you how your day was; you’d tell me it was ‘fine, thank you’.

Or you’d ask me why I decided to move in, why I chose this side of town, this side of town, this apartment building, across from you. That one always ended questionably and I’d rather not explore that one on paper.

My favorites however were the ones where you’d laugh at a stupid pick-up line and somehow we’d end up in your bed. The bed I’ve sat and watched you sleep in. Those were the best additions.

Now, I’ve been fortunate enough that you’ve been loyal, faithful and devoted to only me since the very beginning. So I don’t really have a clue what you’d actually be like in bed.

But god it’s so fun to imagine it.

You’ve got such pretty, soft skin. You let me mar it up with my teeth and soothe it with my tongue. You let me grip the pillowy flesh of your thighs to spread you open for me. You let me pinch and roll and pull your nipples until they were raw and begging for a break. You let me caress the sensitive slick covered folds between those beautiful pussy lips, plunge my fingers in as far as they’d go.

I took you from behind, watching your perky little ass bounce off my cock while I plowed into you. Your face smushed against the couch cushions and your body folded over the arm rest for me to fuck you like the good little girl that you are.

Against the wall with your arms around my neck while I’ve got my hands holding you spread open and in place by the crook of your knees. You promised you stay real still so that I could drill up into you like you deserved.

God damn. Do you know how good you look like that? Back arched against the wall, tits jiggling in my face with every thrust. Your legs pushed up and back to the sides of your torso, to pin you in place?

It was like a pretty pink flower had bloomed and spread its buttery smooth petals just for me.

Don’t even get me started on how good you suck cock. Have you ever been told you could be mistaken for a warm, wet Hoover? No? Didn’t think so cause that would be rude as hell, but I bet someone’s thought it before.

(Me. It’s me, I thought that.)

Fuck those soft lips. Fuck that smooth snake of a tongue. Fuck that tight, hot throat that just loves to take a beating from my dick.

Can’t wait to prove my imagination right.

Speaking of, my dick has been beat. Like actually. If one didn’t know any better they’d assume it’s on life support, but I’m a freak of nature. Cumming upwards of 16 times in the span of 40ish hours would probably put a weaker man in a hospital bed. Or maybe a psych ward.

But I am not a weak man even if my dick feels raw. I’d still fuck you if you asked.

I’d be curious to know if I’d be able to stave off cumming longer from all the abuse or if I’d be so fucking sensitive that I wouldn’t make it in half an inch.

Probably the latter.

Diary Entry: August 2nd

Being so close to you is killing me. Truly it is.

You’ve sunken your claws so deeply into my very soul and you don’t even realize it. It’s torture. To you, I’m just the new guy, nice dude who gave you a book. But to me? You’re my entire world.

I’ve been told I have the personality of a guard dog. Soft and squishy on the inside, dangerous and fierce on the outside. Which I suppose could be true, but really I think it’s for a different reason. For a human, a dog is one small but very impactful blip in your life. But for the dog? You are it’s life.

Am I comparing myself to a dog right now? Yes I am.

I’ll beg for you to throw me the scraps of your affections until you finally toss me a bone.

Bark.

🖤🖤🖤🖤🖤🖤

I’ve been trying my best to give you space. To plan accordingly and in advance. I have our next two interactions simmering on the back burner.

I know that if I go too hard, too fast, you’ll be overwhelmed. That’s the last thing I want. I never want to be the thing that causes you stress, I want to siphon it from you. So, in one week I will set out to help you with a few of your errands and plant a few seeds.

But until then, we have late night snacks and couch chats with Boogie.

I’ve also been doing- you guessed it- more research to do with helpful vitamins and medicines. You’ve responded so well to your SleepyTime tea and since I’ve started making sure your birth control packet is plainly visible in the countertop basket directly beneath that cabinet, you’ve been taking it so well.

I’m so proud of you sweetheart, that’s my girl, look at you taking care of yourself. You’ve done so well in fact, that it’s in my personal opinion that you have earned a very special reward.

Anakin sat on his couch, the live feed of your living room screen mirrored to his Tv. He was watching you cook dinner, he knew you’d be making a stir fry. He’d seen it in your planner, so he’d taken the liberty of ordering himself the same, it’d be here any minute. As would your good friend Sam.

Anakin had originally burned red hot with jealousy at the thought of you inviting a man over to your apartment, that he hadn’t vetted via social media and a quick drop-in. But he was relieved to discover that Sam was just a girl from your book club.

This wasn’t one of his well thought out plans, this was decided upon this morning after you’d returned from book club. So, he was anxious to see if his hunches served him well. Sam seemed like a punctual gal, at least from what he’d seen on social media and the text messages between the two of you from weeks/months before.

Anakin had the wonderful idea to log into your cell service providers website to pull your deleted messages from their data bank. You really should have better passwords.

The thing he was most worried about was his door dasher arriving on time. It was rare that one was too far off on arrival time, but it would be his shit luck and lack of planning that could ruin this little glimpse of you.

The minutes ticked by and he was alerted to the new motion sensors he’d placed near the LED pathway lights on the paved entrance to the apartment building. He quickly switched over to the hallway feed at the front door, seeing that it was his door dasher.

Damn you Trevor. How dare you get there before Sam.

Not to worry, he’d call for the door code and Anakin wouldn’t answer the first time. It wasn’t much but it would buy him a few seconds.

Though it seemed to be that luck was on his side as it often was when it came to you. Sam was so kind, kind enough to let the delivery guy into the building. Which is technically a security concern but Trevor didn’t seem like the type of guy who’d be able to remember a 6 digit door code.

He was too busy staring at your friends ass to pay attention to the numbers she entered anyway.

The footsteps approached your door and his, Anakin waited until he heard Sam knock on your door before he opened his. Trevor stood patiently as Anakin slowly counted out his tip in cash and thankfully you were quick to let your friend inside. After the exchange was complete Anakin gave you a smile and wave.

He could’ve had a heart attack at the response you gave him.

A flirty little finger waggle and smile.

He had to remind himself to breathe and keep his expression a happy-neutral. He’d hate for you to see his blushing cheeks this early on.

“Have a good night girls.” He said as he closed his door and to his surprise you actually answered.

“You too!”

If he weren’t confident that you were a sweet and loving soul, he’d think you were trying to kill him with the siren song of your voice.

Stir fry had never tasted so fucking good.

Diary Entry: July 8th

Grocery day baby, here I come.

I love that you’re so predictable. I love that you’re so fucking cute and always try to strong arm your groceries in one trip. I love that it takes at least two good whacks to the trunk of your shitty old Nissan to properly close it.

It’s cute to watch you struggle with it, the annoyed huffs and angry scowl.

I thought you’d combust on the spot once when your paper grocery bag of flour and sugar ripped open and sent a plume of flour up on your black jeans. The parking lot was very empty and I was very glad because I’d hate for someone to have seen the cursing contest you had with yourself as you picked up your spilled items. Very unladylike you know. But it’s you so I don’t mind, I just like to hear you talk.

It’s almost time. I’ve been sitting in my car for about 10 minutes. Gotta account for the traffic on highway 76. Do you really have to shop all the way out there just because of the Whole Foods? C’mon baby they have the same shit at Kroger.

I’ve been watching your little blue dot on my phone and you’re rounding the corner so I’ll write you later doll.

I love you.

You pulled into the parking lot and sat in your car for a moment. Giving yourself the much need quiet to decompress from your work day and the grocery trip. After you’d checked your messages and scrolled for a moment you decided it was time to head inside before your frozen foods got… not so frozen.

You popped the trunk and fumbled with the faulty latch, your fingers feeling blindly under the metal lip until it finally detached and you were able to open the trunk.

You took a deep breath and scolded yourself for buying the extra few things that could’ve waited till next time. Second trips are for wimps and you weren’t one. So you loaded up your left arm bag by bag until you heard a humored puff of air and the beep of a car locking behind you.

“Need a hand sweetheart?” Anakin grinned, shoving his keys into his front pocket.

He waltzed over and took a few bags off your hands without waiting for a response. It took you aback, not because he hadn’t waited for permission, but because of the way he exuded an odd charm that made you falter.

“Anakin, really it’s alright I can get it.” You said, eyebrows furrowed together in confusion by his kind gesture.

“Mmm no, this seems like a two man mission sweet girl.” He smiled, gathering up a few the last few bags from the trunk and shutting it with one solid push.

“You really don’t have to-“

“I know I don’t have to.” He said tilting his head toward the apartment building to encourage you to walk with him. “I want to.”

“Thank you, that’s… thanks.” You smiled, a light blush creeping across your cheeks.

“Atta girl.” He chuckled, tapping in the door code and holding it open for you despite holding many more bags than you.

Something about the low tone of voice or maybe just the way he looked at you with his icey blue eyes… just sent a chill down your spine. A quick one that was gone in an instant, replaced by a warm glow in the center of your chest.

“Guess chivalry’s not dead.” You joked.

“I’m no knight.” He laughed, “but you’re sure as hell a princess.”

‘Oh that was smooth.’ You thought, trying to ignore the heat at the bottom of your stomach.

What is happening? How on earth can one man be so… everything? Kind, caring, chivalrous and gorgeous to boot.

You felt a wave of embarrassment at the squeaky giggle you let out. He had you tore up from one little comment.

True to the gentleman he seemed to be, he chose not to push it and tease you about your beet red cheeks. He just waited patiently for you as you unlocked your door.

“Do you want me to bring these in for you?” He asked, watching your movements closely.

“Oh that would be great.” You said in relief, leading him into your kitchen.

“Cute little place.” He said, looking around the kitchenette and over to the living room.

He sat down your bags on the counter and started unloading them neatly into rows.

“Oh, you-“

“Mmm mmm.” He shook his head with a smirk, “Just let me help, it’s no big deal.”

You let out a puff of air in an amused sort of amazement and pulled out your little step stool to open up the cabinets. Anakin snickered from behind you as you stepped up and started putting things away.

You shot him a glare over your shoulder and almost said something snarky until you realized he was folding your paper grocery bags in the same way that you always do.

“Huh.” You laughed. “I thought I was the only one who did that.”

“Did what?” He asked, his head cocked to the side.

“Fold the bags.” You said, turning back around to continue placing your things where they belonged.

“Oh,” he chuckled, “I dunno it’s just a habit I guess. Fits better in that stupid slot on the recycling bin this way.”

“Yeah I never really understood why they made them that way? I guess so people don’t just shove other trash in there.” You mused.

“Mmhm probably.” He agreed, stacking them neatly and gathering it in his hands. “Do you want me to take these out back for you?”

“I can do-“ You stopped yourself when Anakin raised his eyebrow and cocked his head to the side with a crooked smirk.

You sighed and gave him a downturned smile. “Yes, I would love for you to take them out back for me.”

“Good girl.” He nodded, clicking his tongue and heading for the door. “See ya princess.”

After he shut the door you let yourself breathe alittle easier, blowing out the air in a short puff through your nose. Maybe even letting a little smile cross your lips before you finished up your task.

You’d be thinking about that low rumble of his voice later. Good girl? Shit.

PART FIVE

Tag-List:

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Let me know if you wanna be added/removed

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literaturepublishers22 · 11 months ago

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Journals Accepting Clinical Images

Clinical Images and Case Reports Journal (CICRJ) is a peer-reviewed high impact factor indexed medical journal established Internationally which provides a platform to publish Clinical Images, Medical Case Reports, Clinical Case Reports, Case Series (series of 2 to 6 cases) and Clinical Videos in Medicine. This is one of clinical images accepting journal in which authors can publish clinical images. Clinical images and case reports journal accepting clnical images for rapid and high quality image publication.

Journal Homepage: https://www.literaturepublishers.org/

The purpose of this clinical imaging journal is to spread the knowledge of novel discoveries and interventions in various fields of clinical imaging science and images in medicine. Medical Image Journal provides a platform for securing visual images concerning medical cases that the physicians come across in all medical subspecialties for better understanding of the disease epidemiology, diagnosis and management.

Manuscript Submission

Authors may submit their manuscripts through the journal's online submission portal: https://www.literaturepublishers.org/submit.html

(or) Send an e-mail attachment to the Editorial Office E-mail Id: [email protected]

#Journals Accepting Clinical Images #health #news #publisher

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literaturepublisher23 · 1 year ago

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Journal of Clinical Images

Journal of Clinical Images accepting articles in the form of clinical images, medical images, clinical images journal, medical images journal, clinical image journal submission. Journal of Clinical Images accepted by Clinical Images and Case Reports Journal with the aim of publishing the clinical images that are related to all the fields of Medicine. The purpose of this journal is to spread the knowledge of novel discoveries and interventions in various fields of science & medicine. The clinical images of fields like surgery, cardiology, dermatology, orthopaedics etc. are included in this journal.

Journal Homepage: https://www.literaturepublishers.org/

Journal of Clinical Images is a peer-reviewed high impact factor journal which has got immense scholarly significance. This journal is being dedicated to the clinical images, medical images, clinical imaging from various areas of medicine. All the latest updates and changes are being included in this clinical image journal. The editorial review process before publishing the clinical journal of clinical images is very strict. All authors are encouraged to submit the clinical images online or by email. The peer review work can be submitted through a set online submission system. The submitted manuscripts are peer reviewed and then checked by various panels of the editors.

Manuscript Submission

Authors may submit their manuscripts through the journal's online submission portal: https://www.literaturepublishers.org/submit.html

(or) Send an e-mail attachment to the Editorial Office E-mail Id: [email protected]

#Journal of Clinical Images #health #publisher #news

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literaturepublisher10 · 1 year ago

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Journal of Clinical Images

Journal Homepage: https://www.literaturepublishers.org/

Manuscript Submission

Authors may submit their manuscripts through the journal's online submission portal: https://www.literaturepublishers.org/submit.html

(or) Send an e-mail attachment to the Editorial Office E-mail Id: [email protected]

#Journal of Clinical Images #news #health #publishers

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literaturepublishersjournal · 1 year ago

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International Clinical Case Reports Journal

Clinical Images and Case Reports Journal is an International clinical case reports journal publishes clinical case reports, case reports in clinical science, journal of clinical case reports etc.

Journal Homepage: https://www.literaturepublishers.org/

International Clinical Case Reports Journal is a crucial source of medical information and our purpose is to enhance global health directly and express an important teaching point on a common or significant clinical scenario and stimulate a more extended quest for evidence. In the broadest context, case reports will encompass the entire range of medicine across health sciences, including all clinical medical specialties, veterinary medicine, nursing, allied health, and dentistry, highlighting an important educational message that is realistic and generalizable.

International Clinical Case Reports Journal is an online peer reviewed international journal purely dedicated to publish genuine and academically valuable case reports that enrich the pre-existing knowledge in the field of medicine. We aim to publish best quality case reports and build a world-class platform for latest information on a specific topic, with contributions from leading experts. International Clinical Case Reports Journal is useful to stay informed on the spectrum of health problems encountered in clinical practice, quality, patient safety, and healthcare systems issues within the scope of the journal. We appreciate receiving case reports, procedural videos, clinical images, and medical case report based reviews from all disciplines of Nursing, Medicine, Dentistry, and Clincial sciences.

Manuscript Submission

Authors may submit their manuscripts through the journal's online submission portal: https://www.literaturepublishers.org/submit.html

(or) Send an e-mail attachment to the Editorial Office E-mail Id: [email protected]

#International Clinical Case Reports Journal #clinical images #medicalcasereportsjournal

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myrawjcsmicasereports · 1 month ago

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Abstract

Introduction

Case Report Presentation

At presentation on March 4, Best Corrected Visual Acuity (BCVA) was reduced at 20/100 OR (20/25 OS). The patient described periods of acutely excruciating retro-orbital pain in the OR. Intraocular pressure was normal, at 12 OR and 18 OS (pachymetry was at 490 microns in both eyes). The dilated fundus examination was similar to the previous color picture and did not disclose peripheral hemorrages recalling extended peripheral retinal ischemia. Humphrey Visual Field disclosed an altitudinal inferior scotoma and a peripheral inferior scotoma OR and was in the normal range OS, i.e. did not recall normal tension glaucoma OS . There were no papillary drusen on the autofluorescence picture, ON volume was increased (11.77 mm3 OR versus 5.75 OS) on SD-OCT (Heidelberg Engineering®) OR, Retinal Nerve Fiber (RNFL) and RGC layers thicknesses were normal Marked epimacular hypereflectivity OR with foveolar depression inversion, moderately increased total volume and central foveolar thickness (CFT) (428 microns versus 328 OS), and a whitish aspect of the supero-temporal internal retinal layers recalling ischemic edema, were present . EDI CFT was incresead at 315 microns (versus 273 microns OS), with focal pachyvessels on the video mapping . OCT-Angiography disclosed focal perfusion defects in both the retinal and chorio-capillaris circulations , and central alterations of the PR1 layer on en-face OCT

On March 4th, the patient was at length informed about the FS, a possible off label rhEPO IVI, and a related written informed consent on the ratio risk-benefits was delivered.

However cystoid ME (CME) had developed . Indo Cyanin Green-Cine Video Angiography (ICG-CVA) OR, performed on March 23, i.e. 16 days after the rhEPO IVI, showed a persistent drop in ocular perfusion: ciliary and central retinal artery perfusion timings were dramatically delayed at respectively 21 and 25 seconds, central retinal vein perfusion initiated by 35 seconds, was pulsatile, and completed by 50 seconds only (video 3). Choroidal pachyveins matching the ones on SD-OCT video mapping were present in the temporal superior and inferior fields, and crossed the macula; capillary exclusion territories were present in the macula and around the optic disc.

A second off label rhEPO IVI was performed in the same conditions on April 3, i.e. approximately one month after the first one.

Last complete follow-up was recorded on January 7, 2021, at 22 months from EPO injection 2. BCVA was at 20/40, ON volume had dropped at 7.46 mm3, a sequaelar superior deficit was present in the RNFL with some corresponding residual defects on the inferior para central Visual Field , CFT was at 384 mm3 with an epimacular hyperreflectivity without ME, EDI CFT was dropped at 230 microns. Perfusion on ICG-CVA was not normalized, but even more improved, with ciliary timing at 15 seconds, central retinal artery at 16 seconds and venous return from 22 to 31 seconds, still pulsatile , indicating that VP was still above IOP. OCT-A showed persisting perfusion voids, especially at the optic disc and within the deep retinal capillary plexus. The latter were present at some degree in the OS as well . Choriocapillaris and PR1 layer were dramatically improved.

Last recorded BCVA was at 20/32 by February 14, 2022, at 34 months from EPO 2. SD-OCT showed stable gliosis hypertrophy and mild alterations of the external layers .

Discussion

Why didn’t we treat the onset of CME by March 18th, i.e. eleven days after EPO IVI 1, by anti-VEGF therapy, the “standard-of-care” in CME for RVO ?

The optimal timing for reperfusion via rhEPO in a non resolved issue:

Conclusion

#off-label therapy #JCRMHS #anti-VEGF therapy #Erythropoietin #Journal of Clinical Case Reports Medical Images and Health Sciences impact factor.#Primary Vascular Dysfunction

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