Astrocyte ß-Adrenergic Receptor Activity Regulates NMDA Receptor Signaling of Medial Prefrontal Cortex Pyramidal Neurons.

Glutamate spillover from the synapse is tightly regulated by astrocytes, limiting the activation of extrasynaptically located NMDA receptors (NMDAR). The processes of astrocytes are dynamic and can modulate synaptic physiology. Though norepinephrine (NE) and ß-adrenergic receptor (ß-AR) activity can modify astrocyte volume, this has yet to be confirmed outside of sensory cortical areas, nor has the effect of noradrenergic signaling on glutamate spillover and neuronal NMDAR activity been explored. We monitored changes to astrocyte process volume in response to noradrenergic agonists in the medial prefrontal cortex of male and female mice. Both NE and the ß-AR agonist isoproterenol (ISO) increased process volume by ∼20%, significantly higher than changes seen when astrocytes had G-protein signaling blocked by GDPßS. We measured the effect of ß-AR signaling on evoked NMDAR currents. While ISO did not affect single stimulus excitatory currents of Layer 5 pyramidal neurons, ISO reduced NMDAR currents evoked by 10 stimuli at 50 Hz, which elicits glutamate spillover, by 18%. After isolating extrasynaptic NMDARs by blocking synaptic NMDARs with the activity-dependent NMDAR blocker MK-801, ISO similarly reduced extrasynaptic NMDAR currents in response to 10 stimuli by 18%. Finally, blocking ß-AR signaling in the astrocyte network by loading them with GDPßS reversed the ISO effect on 10 stimuli-evoked NMDAR currents. These results demonstrate that astrocyte ß-AR activity reduces extrasynaptic NMDAR recruitment, suggesting that glutamate spillover is reduced.

Does the SORG Machine-learning Algorithm for Extremity Metastases Generalize to a Contemporary Cohort of Patients? Temporal Validation From 2016 to 2020.

BACKGROUND: The ability to predict survival accurately in patients with osseous metastatic disease of the extremities is vital for patient counseling and guiding surgical intervention. We, the Skeletal Oncology Research Group (SORG), previously developed a machine-learning algorithm (MLA) based on data from 1999 to 2016 to predict 90-day and 1-year survival of surgically treated patients with extremity bone metastasis. As treatment regimens for oncology patients continue to evolve, this SORG MLA-driven probability calculator requires temporal reassessment of its accuracy. QUESTION/PURPOSE: Does the SORG-MLA accurately predict 90-day and 1-year survival in patients who receive surgical treatment for a metastatic long-bone lesion in a more recent cohort of patients treated between 2016 and 2020? METHODS: Between 2017 and 2021, we identified 674 patients 18 years and older through the ICD codes for secondary malignant neoplasm of bone and bone marrow and CPT codes for completed pathologic fractures or prophylactic treatment of an impending fracture. We excluded 40% (268 of 674) of patients, including 18% (118) who did not receive surgery; 11% (72) who had metastases in places other than the long bones of the extremities; 3% (23) who received treatment other than intramedullary nailing, endoprosthetic reconstruction, or dynamic hip screw; 3% (23) who underwent revision surgery, 3% (17) in whom there was no tumor, and 2% (15) who were lost to follow-up within 1 year. Temporal validation was performed using data on 406 patients treated surgically for bony metastatic disease of the extremities from 2016 to 2020 at the same two institutions where the MLA was developed. Variables used to predict survival in the SORG algorithm included perioperative laboratory values, tumor characteristics, and general demographics. To assess the models' discrimination, we computed the c-statistic, commonly referred to as the area under the receiver operating characteristic (AUC) curve for binary classification. This value ranged from 0.5 (representing chance-level performance) to 1.0 (indicating excellent discrimination) Generally, an AUC of 0.75 is considered high enough for use in clinical practice. To evaluate the agreement between predicted and observed outcomes, a calibration plot was used, and the calibration slope and intercept were calculated. Perfect calibration would result in a slope of 1 and intercept of 0. For overall performance, the Brier score and null-model Brier score were determined. The Brier score can range from 0 (representing perfect prediction) to 1 (indicating the poorest prediction). Proper interpretation of the Brier score necessitates a comparison with the null-model Brier score, which represents the score for an algorithm that predicts a probability equal to the population prevalence of the outcome for each patient. Finally, a decision curve analysis was conducted to compare the potential net benefit of the algorithm with other decision-support methods, such as treating all or none of the patients. Overall, 90-day and 1-year mortality were lower in the temporal validation cohort than in the development cohort (90 day: 23% versus 28%; p < 0.001, and 1 year: 51% versus 59%; p<0.001). RESULTS: Overall survival of the patients in the validation cohort improved from 28% mortality at the 90-day timepoint in the cohort on which the model was trained to 23%, and 59% mortality at the 1-year timepoint to 51%. The AUC was 0.78 (95% CI 0.72 to 0.82) for 90-day survival and 0.75 (95% CI 0.70 to 0.79) for 1-year survival, indicating the model could distinguish the two outcomes reasonably. For the 90-day model, the calibration slope was 0.71 (95% CI 0.53 to 0.89), and the intercept was -0.66 (95% CI -0.94 to -0.39), suggesting the predicted risks were overly extreme, and that in general, the risk of the observed outcome was overestimated. For the 1-year model, the calibration slope was 0.73 (95% CI 0.56 to 0.91) and the intercept was -0.67 (95% CI -0.90 to -0.43). With respect to overall performance, the model's Brier scores for the 90-day and 1-year models were 0.16 and 0.22. These scores were higher than the Brier scores of internal validation of the development study (0.13 and 0.14) models, indicating the models' performance has declined over time. CONCLUSION: The SORG MLA to predict survival after surgical treatment of extremity metastatic disease showed decreased performance on temporal validation. Moreover, in patients undergoing innovative immunotherapy, the possibility of mortality risk was overestimated in varying severity. Clinicians should be aware of this overestimation and discount the prediction of the SORG MLA according to their own experience with this patient population. Generally, these results show that temporal reassessment of these MLA-driven probability calculators is of paramount importance because the predictive performance may decline over time as treatment regimens evolve. The SORG-MLA is available as a freely accessible internet application at https://sorg-apps.shinyapps.io/extremitymetssurvival/ .Level of Evidence Level III, prognostic study.

Cellular mechanisms mediating activity-dependent extracellular space shrinkage in the retina.

Volume transmission plays an essential role in CNS function, with neurotransmitters released from synapses diffusing through the extracellular space (ECS) to distant sites. Changes in the ECS volume fraction (α) will influence the diffusion and the concentration of transmitters within the ECS. We have recently shown that neuronal activity evoked by physiological photic stimuli results in rapid decreases in ECS α as large as 10% in the retina. We now characterize the cellular mechanisms responsible for this ECS shrinkage. We find that block of inwardly rectifying K+ channels with Ba2+ , inhibition of the Na+ /K+ /2Cl- cotransporter with bumetanide, or block of AQP4 water channels with TGN-020 do not diminish the light-evoked ECS decrease. Inhibition of the Na+ /HCO3 - cotransporter by removing HCO3 - from the superfusate, in contrast, reduces the light-evoked ECS decrease by 95.6%. Inhibition of the monocarboxylate transporter with alpha-cyano-4-hydroxycinnamate (4-CIN) also reduces the ECS shrinkage, but only by 32.5%. We tested whether the swelling of Müller cells, the principal glial cells of the retina, is responsible for the light-evoked ECS shrinkage. Light stimulation evoked a 6.3% increase in the volume of the fine processes of Müller cells. This volume increase was reduced by 97.1% when HCO3 - was removed from the superfusate. We conclude that a large fraction of the activity-dependent decrease in ECS α is generated by the activation of the Na+ /HCO3 - cotransporter in Müller cells. The monocarboxylate transporter may also contribute to the response.

Dilation of cortical capillaries is not related to astrocyte calcium signaling.

The brain requires an adequate supply of oxygen and nutrients to maintain proper function as neuronal activity varies. This is achieved, in part, through neurovascular coupling mechanisms that mediate local increases in blood flow through the dilation of arterioles and capillaries. The role of astrocytes in mediating this functional hyperemia response is controversial. Specifically, the function of astrocyte Ca2+ signaling is unclear. Cortical arterioles dilate in the absence of astrocyte Ca2+ signaling, but previous work suggests that Ca2+ increases are necessary for capillary dilation. This question has not been fully addressed in vivo, however, and we have reexamined the role of astrocyte Ca2+ signaling in vessel dilation in the barrel cortex of awake, behaving mice. We recorded evoked vessel dilations and astrocyte Ca2+ signaling in response to whisker stimulation. Experiments were carried out on WT and IP3R2 KO mice, a transgenic model where astrocyte Ca2+ signaling is substantially reduced. Compared to WT mice at rest, Ca2+ signaling in astrocyte endfeet contacting capillaries increased by 240% when whisker stimulation evoked running. In contrast, Ca2+ signaling was reduced to 9% of WT values in IP3R2 KO mice. In all three conditions, however, the amplitude of capillary dilation was largely unchanged. In addition, the latency to the onset of astrocyte Ca2+ signaling lagged behind dilation onset in most trials, although a subset of rapid onset Ca2+ events with latencies as short as 0.15 s occurred. In summary, we found that whisker stimulation-evoked capillary dilations occurred independent of astrocyte Ca2+ increases in the cerebral cortex.

Spatial Organization and Dynamics of the Extracellular Space in the Mouse Retina.

The extracellular space (ECS) plays an important role in the physiology of neural circuits. Despite our detailed understanding of the cellular architecture of the mammalian retina, little is known about the organization and dynamics of the retinal ECS. We developed an optical technique based on two-photon imaging of fluorescently labeled extracellular fluid to measure the ECS volume fraction (α) in the ex vivo retina of male and female mice. This method has high spatial resolution and can detect rapid changes in α evoked by osmotic challenge and neuronal activity. The measured ECS α varied dramatically in different layers of the adult mouse retina, with α equaling ∼0.050 in the ganglion cell layer, ∼0.122 in the inner plexiform layer (IPL), ∼0.025 in the inner nuclear layer (INL), ∼0.087 in the outer plexiform layer, and ∼0.026 in the outer nuclear layer (ONL). ECS α was significantly larger early in retinal development; α was 67% larger in the IPL and 100% larger in the INL in neonatal mice compared with adults. In adult retinas, light stimulation evoked rapid decreases in ECS α. Light-driven reductions in ECS α were largest in the IPL, where visual stimuli decreased α values ∼10%. These light-evoked decreases demonstrate that a physiological stimulus can lead to rapid changes in ECS α and indicate that activity-dependent regulation of extracellular space may contribute to visual processing in the retina.SIGNIFICANCE STATEMENT The volume fraction of the extracellular space (ECS α), that portion of CNS tissue occupied by interstitial space, influences the diffusion of neurotransmitters from the synaptic cleft and the volume transmission of transmitters. However, ECS α has never been measured in live retina, and little is known about how ECS α varies following physiological stimulation. Here we show that ECS α values vary dramatically between different retinal layers and decrease by 10% following light stimulation. ECS α differences within the retina will influence volume transmission and light-evoked α variations may modulate synaptic transmission and visual processing in the retina. Activity-dependent ECS α variations may represent a mechanism of synaptic modulation throughout the CNS.

Regulation of blood flow in diabetic retinopathy.

Blood flow in the retina increases in response to light-evoked neuronal activity, ensuring that retinal neurons receive an adequate supply of oxygen and nutrients as metabolic demands vary. This response, termed "functional hyperemia," is disrupted in diabetic retinopathy. The reduction in functional hyperemia may result in retinal hypoxia and contribute to the development of retinopathy. This review will discuss the neurovascular coupling signaling mechanisms that generate the functional hyperemia response in the retina, the changes to neurovascular coupling that occur in diabetic retinopathy, possible treatments for restoring functional hyperemia and retinal oxygen levels, and changes to functional hyperemia that occur in the diabetic brain.

Not One of the Usual Suspects: MRI Features of Insertional Lateral Cord Plantar Fasciopathy.

OBJECTIVE: The purpose of this article is to report MRI findings of insertional lateral cord plantar fasciopathy and review the presenting symptoms of the condition and suspected diagnoses. CONCLUSION: Lateral cord plantar fasciopathy presents with pain and swelling at the lateral midfoot, which are typically clinically suspected to be caused by fifth metatarsal (MT) base stress fracture of peroneal tendon abnormalities. The MRI findings are identical to those seen in association with the more commonly occurring central cord plantar fasciopathy, which has a calcaneal origin, but the findings affect the insertion of the lateral cord onto the plantar lateral base of the fifth MT.

Glial Cell Calcium Signaling Mediates Capillary Regulation of Blood Flow in the Retina.

UNLABELLED: The brain is critically dependent on the regulation of blood flow to nourish active neurons. One widely held hypothesis of blood flow regulation holds that active neurons stimulate Ca(2+) increases in glial cells, triggering glial release of vasodilating agents. This hypothesis has been challenged, as arteriole dilation can occur in the absence of glial Ca(2+) signaling. We address this controversy by imaging glial Ca(2+) signaling and vessel dilation in the mouse retina. We find that sensory stimulation results in Ca(2+) increases in the glial endfeet contacting capillaries, but not arterioles, and that capillary dilations often follow spontaneous Ca(2+) signaling. In IP3R2(-/-) mice, where glial Ca(2+) signaling is reduced, light-evoked capillary, but not arteriole, dilation is abolished. The results show that, independent of arterioles, capillaries actively dilate and regulate blood flow. Furthermore, the results demonstrate that glial Ca(2+) signaling regulates capillary but not arteriole blood flow. SIGNIFICANCE STATEMENT: We show that a Ca(2+)-dependent glial cell signaling mechanism is responsible for regulating capillary but not arteriole diameter. This finding resolves a long-standing controversy regarding the role of glial cells in regulating blood flow, demonstrating that glial Ca(2+) signaling is both necessary and sufficient to dilate capillaries. While the relative contributions of capillaries and arterioles to blood flow regulation remain unclear, elucidating the mechanisms that regulate capillary blood flow may ultimately lead to the development of therapies for treating diseases where blood flow regulation is disrupted, including Alzheimer's disease, stroke, and diabetic retinopathy. This finding may also aid in revealing the underlying neuronal activity that generates BOLD fMRI signals.

Glial and neuronal control of brain blood flow.

Blood flow in the brain is regulated by neurons and astrocytes. Knowledge of how these cells control blood flow is crucial for understanding how neural computation is powered, for interpreting functional imaging scans of brains, and for developing treatments for neurological disorders. It is now recognized that neurotransmitter-mediated signalling has a key role in regulating cerebral blood flow, that much of this control is mediated by astrocytes, that oxygen modulates blood flow regulation, and that blood flow may be controlled by capillaries as well as by arterioles. These conceptual shifts in our understanding of cerebral blood flow control have important implications for the development of new therapeutic approaches.

Regulation of blood flow in the retinal trilaminar vascular network.

Light stimulation evokes neuronal activity in the retina, resulting in the dilation of retinal blood vessels and increased blood flow. This response, named functional hyperemia, brings oxygen and nutrients to active neurons. However, it remains unclear which vessels mediate functional hyperemia. We have characterized blood flow regulation in the rat retina in vivo by measuring changes in retinal vessel diameter and red blood cell (RBC) flux evoked by a flickering light stimulus. We found that, in first- and second-order arterioles, flicker evoked large (7.5 and 5.0%), rapid (0.73 and 0.70 s), and consistent dilations. Flicker-evoked dilations in capillaries were smaller (2.0%) and tended to have a slower onset (0.97 s), whereas dilations in venules were smaller (1.0%) and slower (1.06 s) still. The proximity of pericyte somata did not predict capillary dilation amplitude. Expression of the contractile protein α-smooth muscle actin was high in arterioles and low in capillaries. Unexpectedly, we found that blood flow in the three vascular layers was differentially regulated. Flicker stimulation evoked far larger dilations and RBC flux increases in the intermediate layer capillaries than in the superficial and deep layer capillaries (2.6 vs 0.9 and 0.7% dilation; 25.7 vs 0.8 and 11.3% RBC flux increase). These results indicate that functional hyperemia in the retina is driven primarily by active dilation of arterioles. The dilation of intermediate layer capillaries is likely mediated by active mechanisms as well. The physiological consequences of differential regulation in the three vascular layers are discussed.

Purinergic control of vascular tone in the retina.

Purinergic control of vascular tone in the CNS has been largely unexplored. This study examines the contribution of endogenous extracellular ATP, acting on vascular smooth muscle cells, in controlling vascular tone in the in vivo rat retina. Retinal vessels were labelled by i.v. injection of a fluorescent dye and imaged with scanning laser confocal microscopy. The diameters of primary arterioles were monitored under control conditions and following intravitreal injection of pharmacological agents. Apyrase (500 units ml(-1)), an ATP hydrolysing enzyme, dilated retinal arterioles by 40.4 ± 2.8%, while AOPCP (12.5 mm), an ecto-5'-nucleotidase inhibitor that increases extracellular ATP levels, constricted arterioles by 58.0 ± 3.8% (P < 0.001 for both), demonstrating the importance of ATP in the control of basal vascular tone. Suramin (500 µm), a broad-spectrum P2 receptor antagonist, dilated retinal arterioles by 50.9 ± 3.7% (P < 0.001). IsoPPADS (300 µm) and TNP-ATP (50 µm), more selective P2X antagonists, dilated arterioles by 41.0 ± 5.3% and 55.2 ± 6.1% respectively (P < 0.001 for both). NF023 (50 µm), a potent antagonist of P2X1 receptors, dilated retinal arterioles by 32.1 ± 2.6% (P < 0.001). A438079 (500 µm) and AZ10606120 (50 µm), P2X7 antagonists, had no effect on basal vascular tone (P = 0.99 and P = 1.00 respectively). In the ex vivo retina, the P2X1 receptor agonist α,ß-methylene ATP (300 nm) evoked sustained vasoconstrictions of 18.7 ± 3.2% (P < 0.05). In vivo vitreal injection of the gliotoxin fluorocitrate (150 µm) dilated retinal vessels by 52.3 ± 1.1% (P < 0.001) and inhibited the vasodilatory response to NF023 (50 µm, 7.9 ± 2.0%; P < 0.01). These findings suggest that vascular tone in rat retinal arterioles is maintained by tonic release of ATP from the retina. ATP acts on P2X1 receptors, although contributions from other P2X and P2Y receptors cannot be ruled out. Retinal glial cells are a possible source of the vasoconstricting ATP.

Oxygen modulation of neurovascular coupling in the retina.

Neurovascular coupling is a process through which neuronal activity leads to local increases in blood flow in the central nervous system. In brain slices, 100% O(2) has been shown to alter neurovascular coupling, suppressing activity-dependent vasodilation. However, in vivo, hyperoxia reportedly has no effect on blood flow. Resolving these conflicting findings is important, given that hyperoxia is often used in the clinic in the treatment of both adults and neonates, and a reduction in neurovascular coupling could deprive active neurons of adequate nutrients. Here we address this issue by examining neurovascular coupling in both ex vivo and in vivo rat retina preparations. In the ex vivo retina, 100% O(2) reduced light-evoked arteriole vasodilations by 3.9-fold and increased vasoconstrictions by 2.6-fold. In vivo, however, hyperoxia had no effect on light-evoked arteriole dilations or blood velocity. Oxygen electrode measurements showed that 100% O(2) raised pO(2) in the ex vivo retina from 34 to 548 mm Hg, whereas hyperoxia has been reported to increase retinal pO(2) in vivo to only ~53 mm Hg [Yu DY, Cringle SJ, Alder VA, Su EN (1994) Am J Physiol 267:H2498-H2507]. Replicating the hyperoxic in vivo pO(2) of 53 mm Hg in the ex vivo retina did not alter vasomotor responses, indicating that although O(2) can modulate neurovascular coupling when raised sufficiently high, the hyperoxia-induced rise in retinal pO(2) in vivo is not sufficient to produce a modulatory effect. Our findings demonstrate that hyperoxia does not alter neurovascular coupling in vivo, ensuring that active neurons receive an adequate supply of nutrients.

Whisker-evoked neurovascular coupling is preserved during hypoglycemia in mouse cortical arterioles and capillaries.

Hypoglycemia is a serious complication of insulin treatment of diabetes that can lead to coma and death. Neurovascular coupling, which mediates increased local blood flow in response to neuronal activity, increases glucose availability to active neurons. This mechanism could be essential for neuronal health during hypoglycemia, when total glucose supplies are low. Previous studies suggest, however, that neurovascular coupling (a transient blood flow increase in response to an increase in neuronal activity) may be reduced during hypoglycemia. Such a reduction in blood flow increase would exacerbate the effects of hypoglycemia, depriving active neurons of glucose. We have reexamined the effects of hypoglycemia on neurovascular coupling by simultaneously monitoring neuronal and vascular responses to whisker stimulation in the awake mouse somatosensory cortex. We find that neurovascular coupling at both penetrating arterioles and at 2nd order capillaries did not change significantly during insulin-induced hypoglycemia compared to euglycemia. In addition, we show that the basal diameter of both arterioles and capillaries increases during hypoglycemia (10.3 and 9.7% increases, respectively). Our results demonstrate that both neurovascular coupling and basal increases in vessel diameter are active mechanisms which help to maintain an adequate supply of glucose to the brain during hypoglycemia.

Astrocyte Regulation of Cerebral Blood Flow in Health and Disease.

Astrocytes play an important role in controlling microvascular diameter and regulating local cerebral blood flow (CBF) in several physiological and pathological scenarios. Neurotransmitters released from active neurons evoke Ca2+ increases in astrocytes, leading to the release of vasoactive metabolites of arachidonic acid (AA) from astrocyte endfeet. Synthesis of prostaglandin E2 (PGE2) and epoxyeicosatrienoic acids (EETs) dilate blood vessels while 20-hydroxyeicosatetraenoic acid (20-HETE) constricts vessels. The release of K+ from astrocyte endfeet also contributes to vasodilation or constriction in a concentration-dependent manner. Whether astrocytes exert a vasodilation or vasoconstriction depends on the local microenvironment, including the metabolic status, the concentration of Ca2+ reached in the endfoot, and the resting vascular tone. Astrocytes also contribute to the generation of steady-state vascular tone. Tonic release of both 20-HETE and ATP from astrocytes constricts vascular smooth muscle cells, generating vessel tone, whereas tone-dependent elevations in endfoot Ca2+ produce tonic prostaglandin dilators to limit the degree of constriction. Under pathological conditions, including Alzheimer's disease, epilepsy, stroke, and diabetes, disruption of normal astrocyte physiology can compromise the regulation of blood flow, with negative consequences for neurological function.

Identification of Gaps in Quality of Care and Good Practice Interventions in Rheumatoid Arthritis: Insights From a Literature Review and Qualitative Study of Nine Centers in North America.

OBJECTIVE: Quality of care (QoC) delivery in rheumatoid arthritis (RA) continues to suffer from various challenges (eg, delay in diagnosis and referral) that can lead to poor patient outcomes. This study aimed to identify good practice interventions that address these challenges in RA care in North America. METHODS: The study was conducted in three steps: (1) literature review of existing publications and guidelines (April 2005 to April 2021) on QoC in RA; (2) in-person visits to >50 individual specialists and health care professionals across nine rheumatology centers in the United States and Canada to identify challenges in RA care and any corresponding good practice interventions; and (3) collation and organization of findings of the two previous methods by commonalities to identify key good practice interventions, followed by further review by RA experts to ensure key challenges and gaps in RA care were captured. RESULTS: Several challenges and eight good practice interventions were identified in RA care. The interventions were prioritized based on the perceived positive impact on the challenges in care and ease of implementation. High-priority interventions included the use of technology to improve care, streamlining specialist treatment, and facilitating comorbidity assessment and care. Other interventions included enabling patient access to optimal medication regimens and improving patient self-management strategies. CONCLUSION: Learnings from the study can be implemented in other rheumatology centers throughout North America to improve RA care. Although the study was completed before the COVID-19 pandemic, the findings remain relevant.

MetaNeuron: A Free Neuron Simulation Program for Teaching Cellular Neurophysiology.

MetaNeuron, a neuron simulation program, is an effective interactive tool for teaching cellular neurophysiology. The computer program simulates a wide range of neuronal behavior in its six lessons: i) Resting Membrane Potential, ii) Membrane Time Constant, iii) Membrane Length Constant, iv) Axon Action Potential, v) Axon Voltage Clamp, and vi) Synaptic Potential. The program is designed foremost as a platform for conducting neurophysiology experiments in silico. Neuronal parameters are easily modified and a virtual stimulator injects single or double current pulses into the neuron. Phenomena such as temporal summation of synaptic potentials, passive spread of a synaptic potential from the dendrite to the soma, the refractory period, families of voltage-clamp traces, and the reversal potential of synaptic responses, are easily illustrated in MetaNeuron. Responses are displayed graphically and can be measured with a cursor. Families of traces can be generated and viewed in rotatable 3D plots. Mac and Windows versions of the program can be downloaded, free of charge, onto individual student computers from the website www.MetaNeuron.org. A manual containing operating instructions, a description of the lessons, and exercises conducted on MetaNeuron, can also be downloaded for free.

Tacrolimus-induced thrombotic microangiopathy: natural history of a severe, acute vasculopathy.

Calcineurin inhibitors (CNI) have been clearly associated with posttransplant thrombotic microangiopathy (PTTMA). We report a case of de novo PT-TMA involving predominantly small arteries and arterioles of a renal allograft in a patient receiving tacrolimus. Serial biopsies demonstrate the natural history of this lesion through the chronic nonspecific phase. The case is discussed in the context of a literature review of PT-TMA in general and CNI use in particular.

Use of a Novel Electronic Auto-Notification Process to Manage Transitions of Care in Patients With Rheumatic Disease Receiving Disease-Modifying Antirheumatic Drug Therapy.

OBJECTIVE: To integrate an auto-notification system into clinical workflow, so timely communication of sentinel events (elective surgery, hospital admission, or emergency room [ER] visit) in immunosuppressed patients with rheumatic disease happened by design. METHODS: We developed an algorithm that triggered auto-notification within the electronic medical record to rheumatology when a patient experienced a sentinel event. A telephone encounter was created that included event type, baseline therapy, and event date. This was forwarded to the rheumatologist, who recorded guideline-driven recommendations and returned it to nursing. Instructions were included to communicate recommendations to the patient, inpatient rheumatology team, or other clinician. This was studied over 4 months at a multispecialty medical practice in Central Pennsylvania. Primary outcomes were percentage of total notifications, notifications by sentinel event type where a change in care plan was recommended, as well as percentage of time where rheumatologists were notified of sentinel events compared to prior to the intervention. The secondary outcome was staff work effort. RESULTS: Two hundred forty notifications were received (57% for elective surgeries, 39% for ER visits, and 4% for admissions). The need for change in care plan was only 17% for ER visits but was 25% for hospital admissions and 44% for elective surgeries. The percentage of time that rheumatologists were notified of events increased from 57.6% to 100%. The average number of messages received per week was 2.2, requiring a weekly average of 13 minutes of work per physician. CONCLUSION: We developed an easy, well-received process that hardwires rheumatologist notification sentinel events to facilitate timely care.

Practical Management for Use of Eculizumab in the Treatment of Severe, Refractory, Non-Thymomatous, AChR + Generalized Myasthenia Gravis: A Systematic Review.

Myasthenia gravis (MG) is a rare autoimmune disorder caused by specific autoantibodies at the neuromuscular junction. MG is classified by the antigen specificity of these antibodies. Acetylcholine receptor (AChR) antibodies are the most common type (74-88%), followed by anti-muscle specific kinase (MuSK) and other antibodies. While all these antibodies lead to neuromuscular transmission failure, the immuno-pathogenic mechanisms are distinct. Complement activation is a primary driver of AChR antibody-positive MG (AChR+ MG) pathogenesis. This leads to the formation of the membrane attack complex and destruction of AChR receptors and the postsynaptic membrane resulting in impaired neurotransmission and muscle weakness characteristic of MG. Broad-based immune-suppressants like corticosteroids are effective in controlling MG; however, their long-term use can be associated with significant adverse effects. Advances in translational research have led to the development of more directed therapeutic agents that are likely to alter the future of MG treatment. Eculizumab is a humanized monoclonal antibody that inhibits the cleavage of complement protein C5 and is approved for use in generalized MG. In this review, we discuss the pathophysiology of MG; the therapeutic efficacy and tolerability of eculizumab, as well as the practical guidelines for its use in MG; future studies exploring the role of eculizumab in different stages and subtypes of MG subtypes; the optimal duration of therapy and its discontinuation; the characterization of non-responder patients; and the use of biomarkers for monitoring therapy are highlighted. Based on the pathophysiologic mechanisms, emerging therapies and new therapeutic targets are also reviewed.