Cosmetic Tourism in Northern Ireland.

AIM: Over the new year period, we recognized a high number of admissions with postoperative complications following cosmetic surgery abroad. We aimed to determine the driving forces behind this and financial impact on the National Health Service (NHS). METHODS: Cases of all patients attending the regional plastic surgery unit with complications following surgery abroad were reviewed. Patients completed a survey on the perioperative period abroad and driving forces. In addition, the costing department was contacted to determine the financial burden associated with cosmetic tourism. RESULTS: Six patients were admitted to the regional unit after independently organizing surgery abroad. Countries visited included Turkey, Belgium, Poland, Estonia, and India. Reasons included cost and access to procedures not recommended by UK surgeon. Type of surgery included breast (5), abdominoplasty (2), liposuction (2), and labiaplasty (1), and 50% had multiple procedures. Complications included necrotic wounds (33%), infected breast implant (33%), venous thromboembolism investigated (33%), and wound infection (17%). Overall, 67% required surgery on the NHS. The total cost was £23,976.82, with an average of £4000/patient (range, £1294-£6291). DISCUSSION/CONCLUSIONS: This surge in cosmetic complications occurred in the New Year period. Complications were seen after a wide range of surgical procedures. All patients required an inpatient stay, and two-thirds required surgery with a significant cost burden to the NHS. Patients are unaware of the risks involved, highlighted by the lack of preoperative counseling and follow-up. In addition, this series has highlighted the risks associated with traveling in the perioperative period, with 2 patients investigated for pulmonary embolus.

Insights into Chronic Functional Movement Disorders: The Value of Qualitative Psychiatric Interviews.

BACKGROUND: Patients with functional movement disorders (FMDs) are commonly seen by neurologists and psychosomatic medicine psychiatrists. Research literature provides scant information about the subjective experiences of individuals with this often chronic problem. OBJECTIVE: To enhance our understanding of psychologic aspects of FMDs by conducting qualitative interviews of research subjects. METHODS: In total, 36 patients with FMDs were recruited from the Human Motor Control clinic at the National Institutes of Health. Each subject participated in a qualitative psychiatric interview and a structured diagnostic psychiatric interview. RESULTS: Of our 36 subjects, 28 had current or lifetime psychiatric disorders in addition to conversion disorder and 22 had current disorders. Qualitative interviews provided rich information on patients' understanding of their illnesses and impaired cognitive processing of emotions. CONCLUSION: Our study supports the addition of open-ended qualitative interviews to delineate emotional dynamics and conceptual frameworks among such patients. Exploratory interviews generate enhanced understanding of such complex patients, above and beyond that gained by assessing DSM diagnostic comorbidities.

Punishing unfairness: rewarding or the organization of a reactively aggressive response?

OBJECTIVES: The neural correlates of human cooperative behavior remain poorly understood. Previous work has suggested that increases in striatal activation while punishing unfair offers represents reward signaling. However, other regions are also implicated when punishing others, for example dorsomedial frontal cortex (dmFC), anterior insula cortex (AIC), and periaqueductal gray (PAG). Moreover, the response of other regions implicated in signaling reward, for example ventromedial prefrontal cortex (vmPFC) or posterior cingulate cortex (PCC), has not been systematically examined. EXPERIMENTAL DESIGN: Functional magnetic resonance imaging utilizing parametric modulation was conducted on 21 healthy adults participating in a social exchange paradigm. PRINCIPAL OBSERVATIONS: Participants showed significant positive modulation of activity as a function of delivered punishment in caudate, dmFC, AIC, and PAG; that is, higher punishments by participants of unsatisfactory offers were associated with increasing activity within these regions. However, participants showed significant negative modulation of activity as a function of delivered punishment in vmPFC and PCC; increases in punishment level by participants were associated with decreases in activity within these regions. CONCLUSIONS: The current data question whether caudate activity when punishing unfair offers should be considered to indicate the reward value of this punishment. Instead, this activity, in conjunction with activity within dmFC, AIC, and PAG, may represent the organization of an untypical, punishing response that represents a reactive aggressive response to provocation. Notably, an inverse, regulatory relationship between vmPFC and PAG activity has been previously implicated in the context of another stimulus for reactive aggression; looming threat (Mobbs et al. [2007]: Science 317:1079-1083).

Safety of transfoveal subthreshold diode micropulse laser for fovea-involving diabetic macular edema in eyes with good visual acuity.

PURPOSE: To determine the safety of transfoveal subthreshold diode micropulse laser for fovea-involving diabetic macular edema. METHODS: The records of all patients treated with transfoveal subthreshold diode micropulse laser for fovea-involving diabetic macular edema in two retina clinics were reviewed. The eligibility included fovea-involving diabetic macular edema by spectral domain optical coherence tomography and pretreatment visual acuity of 20/40 or better. RESULTS: Thirty-nine eyes of 27 patients aged 50 years to 87 years (mean, 69 years) were included. Postoperative follow-up ranged from 3 months to 36 months (mean, 11 months). Fourteen patients were insulin dependent, and 19 had nonproliferative retinopathy. The preoperative visual acuity was 20/20 (10 eyes), 20/25 (10 eyes), 20/30 (8 eyes), and 20/40 (11 eyes). No eye had evidence of laser-induced macular damage by any imaging means postoperatively. There were no adverse treatment effects. Logarithm of the minimum angle of resolution visual acuity was improved on average of 0.03 units at 4 months to 7 months of follow-up (P = 0.0449, paired t-test) and otherwise stable. The central foveal thickness was improved at 4 months to 7 months (P = 0.05, paired t-test) and 8 months to 12 months, postoperatively (P = 0.04, mixed model accounting). Maximum macular thickness was improved at 4 months to 7 months postoperatively (P = 0.01, paired t-test and mixed model accounting). CONCLUSION: In a small retrospective series, transfoveal subthreshold diode micropulse laser was safe and effective for the treatment of fovea-involving diabetic macular edema in eyes with good preoperative visual acuity that were not the candidates for conventional photocoagulation or intravitreal injection. Further study is warranted.

Diabetic retinopathy: New concepts of screening, monitoring, and interventions.

The science of diabetes care has progressed to provide a better understanding of the oxidative and inflammatory lesions and pathophysiology of the neurovascular unit within the retina (and brain) that occur early in diabetes, even prediabetes. Screening for retinal structural abnormalities, has traditionally been performed by fundus examination or color fundus photography; however, these imaging techniques detect the disease only when there are sufficient lesions, predominantly hemorrhagic, that are recognized to occur late in the disease process after significant neuronal apoptosis and atrophy, as well as microvascular occlusion with alterations in vision. Thus, interventions have been primarily oriented toward the later-detected stages, and clinical trials, while demonstrating a slowing of the disease progression, demonstrate minimal visual improvement and modest reduction in the continued loss over prolonged periods. Similarly, vision measurement utilizing charts detects only problems of visual function late, as the process begins most often parafoveally with increasing number and progressive expansion, including into the fovea. While visual acuity has long been used to define endpoints of visual function for such trials, current methods reviewed herein are found to be imprecise. We review improved methods of testing visual function and newer imaging techniques with the recommendation that these must be utilized to discover and evaluate the injury earlier in the disease process, even in the prediabetic state. This would allow earlier therapy with ocular as well as systemic pharmacologic treatments that lower the and neuro-inflammatory processes within eye and brain. This also may include newer, micropulsed laser therapy that, if applied during the earlier cascade, should result in improved and often normalized retinal function without the adverse treatment effects of standard photocoagulation therapy.

The relationship between large cavum septum pellucidum and antisocial behavior, callous-unemotional traits and psychopathy in adolescents.

BACKGROUND: The presence of a large cavum septum pellucidum (CSP) has been previously associated with antisocial behavior/psychopathic traits in an adult community sample. AIMS: The current study investigated the relationship between a large CSP and symptom severity in disruptive behavior disorders (DBD; conduct disorder and oppositional defiant disorder). METHOD: Structural MRI scans of youth with DBDs (N = 32) and healthy comparison youth (N = 27) were examined for the presence of a large CSP and if this was related to symptom severity. RESULTS: Replicating previous results, a large CSP was associated with DBD diagnosis, proactive aggression, and level of psychopathic traits in youth. However, the presence of a large CSP was unrelated to aggression or psychopathic traits within the DBD sample. CONCLUSIONS: Early brain mal-development may increase the risk of a DBD diagnosis, but does not mark a particularly severe form of DBD within patients receiving these diagnoses.

Trends in Language Use During the COVID-19 Pandemic and Relationship Between Language Use and Mental Health: Text Analysis Based on Free Responses From a Longitudinal Study.

BACKGROUND: The COVID-19 pandemic and its associated restrictions have been a major stressor that has exacerbated mental health worldwide. Qualitative data play a unique role in documenting mental states through both language features and content. Text analysis methods can provide insights into the associations between language use and mental health and reveal relevant themes that emerge organically in open-ended responses. OBJECTIVE: The aim of this web-based longitudinal study on mental health during the early COVID-19 pandemic was to use text analysis methods to analyze free responses to the question, "Is there anything else you would like to tell us that might be important that we did not ask about?" Our goals were to determine whether individuals who responded to the item differed from nonresponders, to determine whether there were associations between language use and psychological status, and to characterize the content of responses and how responses changed over time. METHODS: A total of 3655 individuals enrolled in the study were asked to complete self-reported measures of mental health and COVID-19 pandemic-related questions every 2 weeks for 6 months. Of these 3655 participants, 2497 (68.32%) provided at least 1 free response (9741 total responses). We used various text analysis methods to measure the links between language use and mental health and to characterize response themes over the first year of the pandemic. RESULTS: Response likelihood was influenced by demographic factors and health status: those who were male, Asian, Black, or Hispanic were less likely to respond, and the odds of responding increased with age and education as well as with a history of physical health conditions. Although mental health treatment history did not influence the overall likelihood of responding, it was associated with more negative sentiment, negative word use, and higher use of first-person singular pronouns. Responses were dynamically influenced by psychological status such that distress and loneliness were positively associated with an individual's likelihood to respond at a given time point and were associated with more negativity. Finally, the responses were negative in valence overall and exhibited fluctuations linked with external events. The responses covered a variety of topics, with the most common being mental health and emotion, social or physical distancing, and policy and government. CONCLUSIONS: Our results identify trends in language use during the first year of the pandemic and suggest that both the content of responses and overall sentiments are linked to mental health.

Impaired functional but preserved structural connectivity in limbic white matter tracts in youth with conduct disorder or oppositional defiant disorder plus psychopathic traits.

Youths with conduct disorder or oppositional defiant disorder and psychopathic traits (CD/ODD+PT) are at high risk of adult antisocial behavior and psychopathy. Neuroimaging studies demonstrate functional abnormalities in orbitofrontal cortex and the amygdala in both youths and adults with psychopathic traits. Diffusion tensor imaging in psychopathic adults demonstrates disrupted structural connectivity between these regions (uncinate fasiculus). The current study examined whether functional neural abnormalities present in youths with CD/ODD+PT are associated with similar white matter abnormalities. Youths with CD/ODD+PT and comparison participants completed 3.0 T diffusion tensor scans and functional magnetic resonance imaging scans. Diffusion tensor imaging did not reveal disruption in structural connections within the uncinate fasiculus or other white matter tracts in youths with CD/ODD+PT, despite the demonstration of disrupted amygdala-prefrontal functional connectivity in these youths. These results suggest that disrupted amygdala-frontal white matter connectivity as measured by fractional anisotropy is less sensitive than imaging measurements of functional perturbations in youths with psychopathic traits. If white matter tracts are intact in youths with this disorder, childhood may provide a critical window for intervention and treatment, before significant structural brain abnormalities solidify.

Reduced activity within the dorsal endogenous orienting of attention network to fearful expressions in youth with disruptive behavior disorders and psychopathic traits.

Using behavioral and blood oxygen level dependent (BOLD) response indices through functional magnetic resonance imaging (fMRI), the current study investigated whether youths with disruptive behavior disorders (conduct disorder and oppositional defiant disorder) plus psychopathic traits (DBD + PT) show aberrant sensitivity to eye gaze information generally and/or whether they show particular insensitivity to eye gaze information in the context of fearful expressions. The participants were 36 children and adolescents (ages 10-17 years); 17 had DBD + PT and 19 were healthy comparison subjects. Participants performed a spatial attention paradigm where spatial attention was cued by eye gaze in faces displaying fearful, angry, or neutral affect. Eye gaze sensitivity was indexed both behaviorally and as BOLD response. There were no group differences in behavioral response: both groups showed significantly faster responses if the target was in the congruent spatial direction indicated by eye gaze. Neither group showed a Congruence × Emotion interaction; neither group showed an advantage from the displayer's emotional expression behaviorally. However, the BOLD response revealed a significant Group × Congruence × Emotion interaction. The comparison youth showed increased activity within the dorsal endogenous orienting network (superior parietal lobule and inferior parietal sulcus) for fearful congruent relative to incongruent trials relative to the youth with DBD + PT. The results are discussed with reference to current models of DBD + PT and possible treatment innovations.

Diabetes mellitus associated neurovascular lesions in the retina and brain: A review.

Diabetes mellitus (DM) is now recognized as a system-wide, autoimmune, inflammatory, microvascular disorder, which, in the retina and brain results in severe multifocal injury now recognized as a leading cause, world-wide, of progressive vision loss and dementia. To address this problem, resulting primarily from variations in glycemia in the prediabetic and overt diabetic states, it must be realized that, although some of the injury processes associated with diabetes may be system wide, there are varying responses, effector, and repair mechanisms that differ from organ to organ or within varying cell structures. Specifically, within the retina, and similarly within the brain cortex, lesions occur of the "neurovascular unit", comprised of focal microvascular occlusions, inflammatory endothelial and pericyte injury, with small vessel leakage resulting in injury to astrocytes, Müller cells, and microglia, all of which occur with progressive neuronal apoptosis. Such lesions are now recognized to occur before the first microaneurysms are visible to imaging by fundus cameras or before they result in detectable symptoms or signs recognizable to the patient or clinician. Treatments, therefore, which currently are not initiated within the retina until edema develops or there is progression of vascular lesions that define the current staging of retinopathy, and in the brain only after severe signs of cognitive failure. Treatments, therefore are applied relatively late with some reduction in progressive cellular injury but with resultant minimal vision or cognitive improvement. This review article will summarize the multiple inflammatory and remediation processes currently understood to occur in patients with diabetes as well as pre-diabetes and summarize as well the current limitations of methods for assessing the structural and functional alterations within the retina and brain. The goal is to attempt to define future screening, monitoring, and treatment directions that hopefully will prevent progressive injury as well as enable improved repair and attendant function.

The NIMH intramural healthy volunteer dataset: A comprehensive MEG, MRI, and behavioral resource.

The NIMH Healthy Research Volunteer Dataset is a collection of phenotypic data characterizing healthy research volunteers using clinical assessments such as assays of blood and urine, mental health assessments, diagnostic and dimensional measures of mental health, cognitive and neuropsychological functioning, structural and functional magnetic resonance imaging (MRI), along with diffusion tensor imaging (DTI), and a comprehensive magnetoencephalography battery (MEG). In addition, blood samples of healthy volunteers are banked for future analyses. All data collected in this protocol are broadly shared in the OpenNeuro repository, in the Brain Imaging Data Structure (BIDS) format. In addition, task paradigms and basic pre-processing scripts are shared on GitHub. There are currently few open access MEG datasets, and multimodal neuroimaging datasets are even more rare. Due to its depth of characterization of a healthy population in terms of brain health, this dataset may contribute to a wide array of secondary investigations of non-clinical and clinical research questions.

Cardiac MRI to investigate myocardial scar and coronary venous anatomy using a slow infusion of dimeglumine gadobenate in patients undergoing assessment for cardiac resynchronization therapy.

PURPOSE: To evaluate a cardiac MR (CMR) examination with slow infusion of a high-relaxivity contrast agent to visualize coronary venous anatomy (CVA) and myocardial scar in heart failure patients awaiting cardiac resynchronization therapy (CRT). MATERIALS AND METHODS: Fourteen patients awaiting CRT (seven ischemic cardiomyopathy (ICM) and seven non-ICM) and two with normal LV function underwent CMR on a 1.5 Tesla (T) MR scanner. Dimeglumine-gadobenate was slowly infused. Bolus arrival in the LV was measured by a dynamic electrocardiogram (ECG) -triggered inversion recovery (IR) scan subsequent to starting an ECG-triggered respiratory-navigated three-dimensional (3D) SSFP MR scan with IR preparation to acquire systolic whole-heart anatomy for vein visualization. Delayed contrast-enhanced MR scan was performed to assess myocardial scar. CVA obtained by CMR was compared with X-ray venography in 11 patients. CVA and scar were segmented and registered for visual inspection. RESULTS: For all subjects, there was excellent visualization of the CVA. All ICM and one non-ICM patient showed scar. There was excellent correlation between veins seen by CMR and venography. CONCLUSION: We have demonstrated that slow infusion protocol of dimeglumine-gadobenate can be used to assess both CVA and myocardial scar in a single MR examination. Furthermore, an image overlay technique has been used to show the relationship of scar to the CVA.

Effects of intravitreal erythropoietin therapy for patients with chronic and progressive diabetic macular edema.

BACKGROUND AND OBJECTIVE: To determine the effects of intravitreal injections of erythropoietin in eyes with severe, chronic diabetic macular edema, 5 eyes of 5 patients underwent injections of rHuEPO alpha (EPO). PATIENTS AND METHODS: All eyes had progressive vision loss and persistent or worsening edema with prior multi-modal treatment. EPO (5U/50 microL) was injected intravitreally every 6 weeks for three doses and followed for an additional 6 weeks with complete ocular examinations, fluorescein angiography, optical coherence tomography (OCT), and central field acuity perimetry. RESULTS: Visual acuity of all patients was subjectively improved by 3 or more lines in 3 eyes and 1 line in 2 eyes. Visual acuity improved to a larger extent than anatomic improvement by OCT. Clearing of hard exudates but only minor improvement in leakage on fluorescein angiography was observed. Improvement in vision occurred within 1 week after the first injection and was maintained until the end point of the current case series (at 18 weeks after the first injection). CONCLUSION: This case series seems to show a short-term positive response to EPO for a specific group of patients with chronic diabetic macular edema who were unresponsive to currently available therapies.

Path Routing Optimization for STM Ultrasound Rendering.

Ultrasound transducer arrays are capable of producing tactile sensations on the hand, promising hands-free haptic interaction for virtual environments. However, controlling such an array with respect to reproducing a desired perceived interaction remains a challenging problem. In this article, we approach this problem as a dynamic mapping of virtual interactions to existing control metaphors of ultrasound devices, namely, the modulation of focal point positions and intensities over time, a method known as Spatiotemporal Modulation (STM). In particular, we propose an optimization approach that takes into account known perceptual parameters and limitations of the STM method. This results in a set of focal point paths optimized to best reconstruct an arbitrary target pressure field.

Slowed Progression of Age-Related Geographic Atrophy Following Subthreshold Laser.

PURPOSE: To determine the effect of panmacular low-intensity/high-density subthreshold diode micropulse laser (SDM) on age-related geographic atrophy (ARGA) progression. METHODS: The retinal images of all eyes with ARGA in a previously reported database, consisting of all eyes with dry age-related macular degeneration (AMD) active in a vitreoretinal practice electronic medical record (EMR), were identified and analyzed to determine the velocity of radial linear ARGA progression during observation and after panmacular SDM. RESULTS: Sixty-seven eyes of 49 patients with ARGA, mean age of 86 years were identified as having follow-up both before and after initiation of SDM treatment. All were included in the study. These eyes were followed a mean 910 days (2.5 years) prior to SDM treatment and a mean 805 days (2.2 years) after. Measurement masked to treatment vs observation found the radius of ARGA lesions progressed 1 to 540 µm per year (mean 137µm, SD 107) prior to treatment (controls); and -44 to 303 µm per year (mean 73µm, SD 59) after initiation of periodic panmacular SDM laser. Thus, the velocity of radial linear progression decreased 47% per year following panmacular SDM (p<0.0001). There were no adverse treatment effects. CONCLUSION: In cohort of eyes with high-risk dry AMD, panmacular SDM slowed linear radial ARGA progression velocity 47% per year (p<0.0001) without adverse treatment effects. Validated, these findings would constitute an important advance in the prevention of age-related visual loss and a benchmark for future therapies.

Utilization of the DSM-5 Self-Rated Level 1 Cross-Cutting Symptom Measure-Adult to Screen Healthy Volunteers for Research Studies.

The DSM-5 Level 1 Cross-Cutting Symptom Measure-Adult (DSM XC) was developed by the American Psychiatric Association (APA) as a transdiagnostic measure of current mental health symptomatology. This paper describes utilization of the DSM XC to screen volunteers for participation in mental health research studies as healthy controls. Research volunteers completed an online, modified version of the DSM XC, which along with other clinical information, was used to determine eligibility for participation as a healthy control. The sensitivity and specificity of screening positive on the DSM XC for this eligibility decision were calculated. Of 506 volunteers who completed the screening process, 159 (31%) were ineligible due to mental health reasons. The DSM XC sensitivity in predicting this determination was 64.2% [95% CI: 56.5 - 71.3] and its specificity was 83.9% [95% CI: 79.7 - 87.5]. When DSM XC responses were combined with information about current psychotropic medication use, an important determinant of study eligibility, the sensitivity improved to 81.8% [95% CI: 75.3 - 87.2). These findings provide preliminary support for the use of the DSM XC as an initial screening tool for mental health studies that enroll healthy research volunteers, particularly when supplemented by additional clinical history such as psychotropic medication use.

Entoptic phenomenon following pars plana vitrectomy caused by retained preretinal gel.

A patient who underwent pars plana vitrectomy for vitreous floaters is described. At the time of surgery, the posterior hyaloid was avulsed and stripped from the posterior retinal surface. Postoperatively, the patient described filamentous and "sea-fan" entoptic phenomena scattered throughout the periaxial vision that were in focus, attached, and "waving" with movement that was counter to the direction of gaze pursuit and demonstrated after movement. The authors believe these structures represent vitreous gel retained at the retinal surface, even though the structures could not be demonstrated by optical coherence tomography or indocyanine green staining at later vitrectomy surgery. This case should raise caution when considering vitrectomy surgery that requires posterior hyaloid stripping in patients with good vision.

Diabetic Retinopathy-An Underdiagnosed and Undertreated Inflammatory, Neuro-Vascular Complication of Diabetes.

Diabetes mellitus is a world-wide epidemic and diabetic retinopathy, a devastating, vision-threatening condition, is one of the most common diabetes-specific complications. Diabetic retinopathy is now recognized to be an inflammatory, neuro-vascular complication with neuronal injury/dysfunction preceding clinical microvascular damage. Importantly, the same pathophysiologic mechanisms that damage the pancreatic ß-cell (e.g., inflammation, epigenetic changes, insulin resistance, fuel excess, and abnormal metabolic environment), also lead to cell and tissue damage causing organ dysfunction, elevating the risk of all complications, including diabetic retinopathy. Viewing diabetic retinopathy within the context whereby diabetes and all its complications arise from common pathophysiologic factors allows for the consideration of a wider array of potential ocular as well as systemic treatments for this common and devastating complication. Moreover, it also raises the importance of the need for methods that will provide more timely detection and prediction of the course in order to address early damage to the neurovascular unit prior to the clinical observation of microangiopathy. Currently, treatment success is limited as it is often initiated far too late and after significant neurodegeneration has occurred. This forward-thinking approach of earlier detection and treatment with a wider array of possible therapies broadens the physician's armamentarium and increases the opportunity for prevention and early treatment of diabetic retinopathy with preservation of good vision, as well the prevention of similar destructive processes occurring among other organs.

Intravitreal injection of erythropoietin protects both retinal vascular and neuronal cells in early diabetes.

PURPOSE: To explore and evaluate the protective effect of erythropoietin (EPO) on retinal cells of chemically induced diabetic rats after EPO was injected intravitreally at the onset of diabetes. METHODS: Diabetes was induced in Sprague-Dawley rats by intraperitoneal injection of streptozotocin (STZ). At the onset of diabetes, a single intravitreal injection of EPO (0.05-200 ng/eye) was performed. In the following 6 weeks, the blood retinal barrier (BRB) was evaluated by Evans blue permeation (EBP). Retinal cell death in different layers was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining. The retinal thickness and cell counts were examined at the light microscopic level. Electron microscopy (EM) was used to scrutinize retinal vascular and neuronal injury. Neurosensory retinas of normal and diabetic rats were used as the sources of reverse transcription-polymerase chain reaction (RT-PCR) and Western blot for the detection of EPO, EPO receptor (EpoR), and products of the extracellular signal-regulated kinase (ERK) and the signal transducers and activators of transcription 5 (STAT5) pathways. The distribution of EpoR in retinal layers was demonstrated by immunohistochemistry (IHC). RESULTS: In the diabetic rats, BRB breakdown was detected soon after the onset of diabetes, peaked at 2 weeks, and reached a plateau at 2 to 4 weeks. The number of TUNEL-positive cells increased in the neurosensory retina, especially, the outer nuclear layer (ONL) at 1 week after diabetes onset and reached a peak at 4 to 6 weeks. The retinal thickness and the number of cells in the ONL were reduced significantly. EM observations demonstrated vascular and photoreceptor cell death starting soon after the onset of diabetes. All these changes were largely prevented by EPO treatment. Upregulation of EpoR in the neurosensory retina was detected at both the transcriptional and protein levels 4 to 8 weeks after the onset of diabetes, whereas, the endogenous EPO levels of neurosensory retinas were essentially unchanged during the same period observed. In EPO-treated diabetic groups, EpoR expression remained at upregulated levels. Within 2 weeks of the onset of diabetes, activation of the ERK but not the STAT5 pathway was detected in the diabetic retina treated with EPO. CONCLUSIONS: These data demonstrate that apoptosis is an major contributor to neuronal cell death in the early course of diabetic retinopathy (DR). The upregulation of EpoR may be a compensatory response of retinal cells and tissue to diabetic stresses. The EPO/EpoR system as a maintenance-survival mechanism of retinal neurons responds to the insults of early diabetes other than ischemia. The protective function of EPO/EpoR at the least acts through the EpoR-mediated ERK pathway. Exogenous EPO administration by intravitreal injection in early diabetes may prevent retinal cell death and protect the BRB function. Therefore, this is a novel approach for treatment of early DR.

Pharmacokinetic and toxicity study of intravitreal erythropoietin in rabbits.

AIM: To study the pharmacokinetics and toxicity of intravitreal erythropoietin (EPO) for potential clinical use. METHODS: For toxicity study, 4 groups (60 rabbits) with intravitreal injection (IVit) of EPO were studied (10 U, 100 U, or 1,000 U) per eye for single injection and 0.6 U/eye (the designed therapeutic level in rabbits) for monthly injections (6X). Eye examination, flash electroretinogram (ERG), and fluorescein angiography (FA) were carried out before and after injection. The rabbits were killed for histological study at different intervals. For the pharmacokinetic study, after IVit of 5 U EPO into left eyes, 44 rabbits were killed at different intervals, and the EPO levels in vitreous, aqueous, retina and serum were analyzed by enzyme-linked immunosorbent assay. RESULTS: At all of the time points examined, the eyes were within normal limits. No significant ERG or FA change was observed. The histology of retina remained unchanged. The pharmacokinetic profile of EPO in ocular compartments was summarized as follows. The half-life times of EPO in vitreous, aqueous and serum were 2.84, 3.24 and 2.12 d, respectively; and Cmax were 4615.75, 294.31 and 1.60 U/L, respectively. EPO concentrations in the retina of the injected eye peaked at 1.36 U/g protein at 6 h following injection, with the half-life observed to be 3.42 d. CONCLUSIONS: IVit of EPO in a wide range is well tolerated and safe for rabbit eyes. At doses up to 10-fold higher than therapeutic levels, EPO has a pharmacokinetic profile with faster clearance, which is favorable for episodic IVit.