The Real-World Effect of Intravitreous Anti-Vascular Endothelial Growth Factor Drugs on Intraocular Pressure: An Analysis Using the IRIS Registry.

PURPOSE: To identify sustained differences in intraocular pressure (IOP) after intravitreous injections of anti-vascular endothelial growth factor (VEGF) drugs. DESIGN: Database study. PARTICIPANTS: Patients seeing an ophthalmic provider who contributes to the database. METHODS: We identified a total of 23 776 unique patients who received only a single type of anti-VEGF medication (bevacizumab, aflibercept, or ranibizumab) by injection in the right eye in the American Academy of Ophthalmology Intelligent Research in Sight Registry. Subgroups included patients with age-related macular degeneration only and patients who had not received an anti-VEGF injection for at least 1 year before the study. We examined those with at least 12, 18, and 25 injections for each of these 3 medications. For all groups, we used fellow, untreated eyes for comparison. MAIN OUTCOME MEASURES: The mean change in IOP from baseline at a minimum of 1 year of follow-up and the proportion of eyes with a clinically significant IOP increase (defined as sustained rise of at least 6 mmHg to an IOP of more than 21 mmHg). RESULTS: All patients in all groups receiving all drugs showed a decrease in IOP from baseline, with a mean of 0.9 mmHg in treated eyes compared with an average decrease of 0.2 mmHg in fellow untreated eyes, a statistically significant difference. A generalized linear model accounting for confounders associated bevacizumab with slightly less lowering of IOP than aflibercept and ranibizumab in most subgroups. A clinically significant IOP increase was seen in 2.6% of eyes receiving injections compared with 1.5% in the associated untreated fellow eyes. Clinically significant IOP increases occurred at a rate of 1.9%, 2.8%, and 2.8% for aflibercept, ranibizumab, and bevacizumab, respectively, which was significantly higher than untreated fellow eyes for bevacizumab and ranibizumab, but not for aflibercept. CONCLUSIONS: These analyses from real-world data indicate that anti-VEGF intravitreous injections are associated with a small but statistically significant decrease in IOP over time. A proportion of patients, on average 2.6%, experienced a sustained clinically significant IOP rise with these drugs overall compared with 1.5% in the fellow untreated eyes. However, such an increase was not seen with aflibercept.

Modulation of serotonin dynamics in the dorsal raphe nucleus via high frequency medial prefrontal cortex stimulation.

The subcallosal cingulate (SCC) region, or its rodent homologue the medial prefrontal cortex (mPFC), and midbrain dorsal raphe (DR) are crucial nodes of the widespread network implicated in emotional regulation. Stimulation of the SCC is being explored as a potential treatment for depression. Because modulation of the 5-HT system is the most common pharmacological means of treating depression, we sought to establish 5-HT's role in the mPFC-DR projection. Using anaesthetized mice, we recorded neuronal activity in 49 neurons of the DR before, during, and after high frequency stimulation (HFS) of the mPFC. The majority of DR cells (74%) significantly decreased firing rate during HFS (p<0.001, 65.7±9.4% of baseline, 14 mice). To see the effect of mPFC-HFS on 5-HT neurons, we used transgenic mice with expression of the channelrhodopsin fusion protein directed to the 5-HT neuronal population. Neurons were categorized as 5-HT based on their excitatory response to blue light stimulation (p<0.05, n=11). Our main finding was that identified 5-HT neurons in the DR were clearly inhibited by HFS, albeit non-selectively. Lastly, we used fast scan cyclic voltammetry (FSCV) to investigate the effects of mPFC-HFS on the release and reuptake of electrically stimulated 5-HT in the DR of C57BL/6J mice. Serotonin clearance was significantly faster following 5min HFS (2.3±1.0s, n=5, p<0.05) when compared to control levels (3.7±1.0s, n=5), indicating less release or more efficient 5-HT reuptake. Taken together, these findings imply that mPFC stimulation alters 5-HT activity dynamics in the DR. Such altered 5-HT dynamics may modulate the potential therapeutic mechanisms of SCC/mPFC stimulation.

In vivo histamine voltammetry in the mouse premammillary nucleus.

Histamine plays a major role in the mediation of allergic reactions such as peripheral inflammation. This classical monoamine is also a neurotransmitter involved in the central nervous system but its role in this context is poorly understood. Studying histamine neurotransmission is important due to its implications in many neurological disorders. The sensitivity, selectivity and high temporal resolution of fast scan cyclic voltammetry (FSCV) offer many advantages for studying electroactive neurotransmitters. Histamine has previously been studied with FSCV; however, the lack of a robust Faradaic electrochemical signal makes it difficult to selectively identify histamine in complex media, as found in vivo. In this work, we optimize an electrochemical waveform that provides a stimulation-locked and unique electrochemical signal towards histamine. We describe in vitro waveform optimization and a novel in vivo physiological model for stimulating histamine release in the mouse premammillary nucleus via stimulation of the medial forebrain bundle. We demonstrate that a robust signal can be used to effectively identify histamine and characterize its in vivo kinetics.

The coaction of tonic and phasic dopamine dynamics.

Tonic neurochemical dopamine activity underlies many brain functions; however a consensus on this important concentration has not yet been reached. In this work, we introduce in vivo fast-scan controlled-adsorption voltammetry to report tonic dopamine concentrations (90 ± 9 nM) and the dopamine diffusion coefficient (1.05 ± 0.09 × 10(-6) cm(2) s(-1)) in the mouse brain.

Improved Calibration of Voltammetric Sensors for Studying Pharmacological Effects on Dopamine Transporter Kinetics in Vivo.

The distribution and density of neurons within the brain poses many challenges when making quantitative measurements of neurotransmission in the extracellular space. A volume neurotransmitter is released into the synapse during chemical communication and must diffuse through the extracellular space to an implanted sensor for real-time in situ detection. Fast-scan cyclic voltammetry is an excellent technique for measuring biologically relevant concentration changes in vivo; however, the sensitivity is limited by mass-transport-limited adsorption. Due to the resistance to mass transfer in the brain, the response time of voltammetric sensors is increased, which decreases the sensitivity and the temporal fidelity of the measurement. Here, experimental results reveal how the tortuosity of the extracellular space affects the response of the electrode. Additionally, a model of mass-transport-limited adsorption is utilized to account for both the strength of adsorption and the magnitude of the diffusion coefficient to calculate the response time of the electrode. The response time is then used to determine the concentration of dopamine released in response to salient stimuli. We present the method of kinetic calibration of in vivo voltammetric data and apply the method to discern changes in the KM for the murine dopamine transporter. The KM increased from 0.32 ± 0.08 µM (n = 3 animals) prior to drug administration to 2.72 ± 0.37 µM (n = 3 animals) after treatment with GBR-12909.

Voltammetric and mathematical evidence for dual transport mediation of serotonin clearance in vivo.

The neurotransmitter serotonin underlies many of the brain's functions. Understanding serotonin neurochemistry is important for improving treatments for neuropsychiatric disorders such as depression. Antidepressants commonly target serotonin clearance via serotonin transporters and have variable clinical effects. Adjunctive therapies, targeting other systems including serotonin autoreceptors, also vary clinically and carry adverse consequences. Fast scan cyclic voltammetry is particularly well suited for studying antidepressant effects on serotonin clearance and autoreceptors by providing real-time chemical information on serotonin kinetics in vivo. However, the complex nature of in vivo serotonin responses makes it difficult to interpret experimental data with established kinetic models. Here, we electrically stimulated the mouse medial forebrain bundle to provoke and detect terminal serotonin in the substantia nigra reticulata. In response to medial forebrain bundle stimulation we found three dynamically distinct serotonin signals. To interpret these signals we developed a computational model that supports two independent serotonin reuptake mechanisms (high affinity, low efficiency reuptake mechanism, and low affinity, high efficiency reuptake system) and bolsters an important inhibitory role for the serotonin autoreceptors. Our data and analysis, afforded by the powerful combination of voltammetric and theoretical methods, gives new understanding of the chemical heterogeneity of serotonin dynamics in the brain. This diverse serotonergic matrix likely contributes to clinical variability of antidepressants.

Fast-scan cyclic voltammetry analysis of dynamic serotonin reponses to acute escitalopram.

The treatment of depression with selective serotonin reuptake inhibitors, SSRIs, is important to study on a neurochemical level because of the therapeutic variability experienced by many depressed patients. We employed the rapid temporal capabilities of fast scan cyclic voltammetry at carbon fiber microelectrodes to study the effects of a popular SSRI, escitalopram (ESCIT), marketed as Lexapro, on serotonin in mice. We report novel, dynamic serotonin behavior after acute ESCIT doses, characterized by a rapid increase in stimulated serotonin release and a gradual rise in serotonin clearance over 120 min. Dynamic changes after acute SSRI doses may be clinically relevant to the pathology of increased depression or suicidality after onset of antidepressant treatment. Due to the short-term variability of serotonin responses after acute ESCIT, we outline difficulties in creating dose response curves and we suggest effective means to visualize dynamic serotonin changes after SSRIs. Correlating chemical serotonin patterns to clinical findings will allow a finer understanding of SSRI mechanisms, ultimately providing a platform for reducing therapeutic variability.

Brain dopamine and serotonin differ in regulation and its consequences.

Dopamine and serotonin (5-hydroxytryptamine or 5-HT) are neurotransmitters that are implicated in many psychological disorders. Although dopamine transmission in the brain has been studied extensively in vivo with fast scan cyclic voltammetry, detection of 5-HT using in vivo voltammetric methods has only recently been established. In this work we use two carbon-fiber microelectrodes to simultaneously measure dopamine release in the nucleus accumbens and 5-HT release in the substantia nigra pars reticulata, using a common stimulation in a single rat. We find that 5-HT release is profoundly restricted in comparison with dopamine release despite comparable tissue content levels. Using physiological and pharmacological analysis, we find that 5-HT transmission is mostly sensitive to uptake and metabolic degradation mechanisms. In contrast, dopamine transmission is constrained by synthesis and repackaging. Finally, we show that disruption of serotonergic regulatory mechanisms by simultaneous inhibition of uptake and metabolic degradation can have severe physiological consequences that mimic serotonin syndrome.

In vivo electrochemical evidence for simultaneous 5-HT and histamine release in the rat substantia nigra pars reticulata following medial forebrain bundle stimulation.

Exploring the mechanisms of serotonin [5-hydroxytryptamine (5-HT)] in the brain requires an in vivo method that combines fast temporal resolution with chemical selectivity. Fast-scan cyclic voltammetry is a technique with sufficient temporal and chemical resolution for probing dynamic 5-HT neurotransmission events; however, traditionally it has not been possible to probe in vivo 5-HT mechanisms. Recently, we optimized fast-scan cyclic voltammetry for measuring 5-HT release and uptake in vivo in the substantia nigra pars reticulata (SNR) with electrical stimulation of the dorsal raphe nucleus (DRN) in the rat brain. Here, we address technical challenges associated with rat DRN surgery by electrically stimulating 5-HT projections in the medial forebrain bundle (MFB), a more accessible anatomical location. MFB stimulation elicits 5-HT in the SNR; furthermore, we find simultaneous release of an additional species. We use electrochemical and pharmacological methods and describe physiological, anatomical and independent chemical analyses to identify this species as histamine. We also show pharmacologically that increasing the lifetime of extracellular histamine significantly decreases 5-HT release, most likely because of increased activation of histamine H-3 receptors that inhibit 5-HT release. Despite this, under physiological conditions, we find by kinetic comparisons of DRN and MFB stimulations that the simultaneous release of histamine does not interfere with the quantitative 5-HT concentration profile. We therefore present a novel and robust electrical stimulation of the MFB that is technically less challenging than DRN stimulation to study 5-HT and histamine release in the SNR.

Achieving compliance with medical call centers.

Providers that retain outside call centers for physician referral should take steps to ensure compliance with Federal and state antikickback statutes. The Federal antikickback statute implicates call centers that offer referral services. A Federal safe harbor permits arrangements between participants and a referral service under specified circumstances. State antikickback statutes and safe harbors may vary from those under Federal law. A provider may not escape responsibility for compliance by contracting with call-center vendors. Providers and call-center vendors should work together to understand and comply with relevant statutes.

Learning disability subtypes: classification of high functioning hyperlexia.

This study examined 30 children with hyperlexic reading patterns and average intelligence to determine if established learning disability subtypes could be applied to these children with hyperlexia. Two groups emerged. One type showed language learning disorder patterns with good visual memory. This group also showed a high percentage of phonetic word errors. A second hyperlexic group showed signs of nonverbal learning disorder with visual spatial deficits and impaired visual memory. This latter subgroup showed few phonetic errors with more sight word errors. These findings suggest subtypes of high functioning hyperlexia, one showing language deficits characteristic of dysphasia and one showing patterns similar to visual spatial dyslexia.