Objective
To report initial results of a planned multicenter year‐long prospective study examining the risk and impact of COVID‐19 among persons with neuroinflammatory disorders (NID), particularly ...multiple sclerosis (MS).
Methods
In April 2020, we deployed online questionnaires to individuals in their home environment to assess the prevalence and potential risk factors of suspected COVID‐19 in persons with NID (PwNID) and change in their neurological care.
Results
Our cohort included 1115 participants (630 NID, 98% MS; 485 reference) as of 30 April 2020. 202 (18%) participants, residing in areas with high COVID‐19 case prevalence, met the April 2020 CDC symptom criteria for suspected COVID‐19, but only 4% of all participants received testing given testing shortages. Among all participants, those with suspected COVID‐19 were younger, more racially diverse, and reported more depression and liver disease. PwNID had the same rate of suspected COVID‐19 as the reference group. Early changes in disease management included telemedicine visits in 21% and treatment changes in 9% of PwNID. After adjusting for potential confounders, increasing neurological disability was associated with a greater likelihood of suspected COVID‐19 (ORadj = 1.45, 1.17–1.84).
Interpretations
Our study of real‐time, patient‐reported experience during the COVID‐19 pandemic complements physician‐reported MS case registries which capture an excess of severe cases. Overall, PwNID seem to have a risk of suspected COVID‐19 similar to the reference population.
Objective: To establish a detailed technical procedure for studying the anatomical correlates of chronic cerebrospinal venous insufficiency in cadavers of multiple sclerosis and control subjects, and ...to present our findings of the normal anatomic venous structures, with reference to previous descriptions from the literature.
Methods: This study examined the internal jugular veins (IJVs), the brachiocephalic veins, and the azygos vein from 20 cadavers (10 control and 10 multiple sclerosis). These veins were exposed, isolated by clamps from the rest of the venous system, flushed with water, and then injected with fluid silicone from the superior ends of both IJVs. After the silicone cured to its solid state, the venous tree was removed en bloc and dissected longitudinally to expose the luminal surface. All vein segments were analyzed for anatomic variation. Anatomical analysis for this manuscript focused on normal vein architecture and its variants.
Results: Thirty-seven of 40 IJVs contained valves: 29 bicuspid, 6 tricuspid, and 2 unicuspid. The average circumferences of the right and left IJVs were 2·2 and 1·8 cm, respectively. Thirteen of 20 azygos veins contained a valve, located on average 3·6 cm away from the superior vena cava junction. Nine of the 13 azygos valves were bicuspid; four were tricuspid. Only one of the 40 brachiocephalic veins contained a valve.
Discussion: We detailed a technical approach for harvesting cadaveric neck and thoracic veins with relevance to chronic cerebrospinal venous insufficiency. The anatomy of the venous system has significant variability, including differing number of valves in different regions and variable characteristics of the valves. Average vein circumference was less than that typically reported in imaging studies of live patients.
Opinion statement
Multiple sclerosis (MS) is a relapsing and progressive disorder of the central nervous system. It is characterized most commonly by episodes of clinical worsening, followed by ...clinical improvement. Pathologically, MS is associated with focal areas of myelin destruction, inflammation, and axonal transection (“demyelinating plaques”) in the brain and spinal cord. Traditionally, MS has been considered an autoimmune disorder, with the primary pathophysiology arising from an errant immune system. Recent work has raised the possibility that MS is not caused primarily by an immune abnormality but may instead arise from venous anomalies affecting the jugular and/or azygos venous systems. This condition has been called chronic cerebrospinal venous insufficiency (CCSVI). It has been proposed that CCSVI may be pathogenic in MS, causing venous back pressure and iron deposition, with a secondary immune response. Some investigators have proceeded to unblinded nonrandomized angioplasty and stenting procedures in patients with CCSVI, with anecdotal reports of symptom improvement. Because of conflicting data on the presence of CCSVI and the absence of controlled trials of CCSVI intervention, the current standard of clinical care is neither to evaluate multiple sclerosis (MS) patients for CCSVI anomalies, nor to intervene with procedures to alter such anomalies. There is intense interest and ongoing work to evaluate the presence of venous anomalies in MS patients as well as in normal controls and patients with other neurologic conditions; to characterize such anomalies, if present; and to further understand whether the concept of a “backpressure” pathology is borne out by the evidence. If CCSVI is indeed a pathogenic mechanism for some subset of the MS population, this would dramatically change the focus of attention for therapeutic endeavors and monitoring for this population and would bring MS therapeutics firmly into the area of vascular intervention. On the other hand, the history of MS research contains many novel and potentially paradigm-shifting ideas that were later disproved by other investigators.
We sought to determine the effect of hydration on the criteria for chronic cerebrospinal venous insufficiency (CCSVI), a proposed hypothesis for the etiology of multiple sclerosis (MS). Sixteen ...subjects (11 MS and 5 controls) were asked to fast overnight. The following morning, 2 CCSVI ultrasound examinations were performed: 1 in the mildly dehydrated state, and another 30-45 minutes after rehydrating with 1.5 L of Gatorade. Seven subjects fulfilled CCSVI criteria in the dehydrated state. Of these, 5 (71%) no longer fulfilled CCSVI criteria after rehydration. One additional subject met CCSVI criteria only after rehydration. Hydration status has a substantial effect on CCSVI criteria, suggesting that the sonographic findings of CCSVI may represent a physiologic rather than pathologic state.
To identify factors associated with grade ≥3 treatment related late esophageal toxicity after lung or liver stereotactic body radiation therapy (SBRT).
This was a retrospective review of 52 patients ...with a planning target volume within 2 cm of the esophagus from a prospective registry of 607 lung and liver SBRT patients treated between 2005 and 2011. Patients were treated using a risk-adapted dose regimen to a median dose of 50 Gy in 5 fractions (range, 37.5-60 Gy in 3-10 fractions). Normal structures were contoured using Radiation Therapy Oncology Group (RTOG) defined criteria.
The median esophageal point dose and 1-cc dose were 32.3 Gy (range, 8.9-55.4 Gy) and 24.0 Gy (range, 7.8-50.9 Gy), respectively. Two patients had an esophageal fistula at a median of 8.4 months after SBRT, with maximum esophageal point doses of 51.5 and 52 Gy, and 1-cc doses of 48.1 and 50 Gy, respectively. These point and 1-cc doses were exceeded by 9 and 2 patients, respectively, without a fistula. The risk of a fistula for point doses exceeding 40, 45, and 50 Gy was 9.5% (n=2/21), 10.5% (n=2/19), and 12.5% (n=2/16), respectively. The risk of fistula for 1-cc doses exceeding 40, 45, and 50 Gy was 25% (n=2/9), 50% (n=2/4), and 50% (n=2/4), respectively. Eighteen patients received systemic therapy after SBRT (11 systemic chemotherapy, and 6 biologic agents, and 1 both). Both patients with fistulas had received adjuvant anti-angiogenic (vascular endothelial growth factor) agents within 2 months of completing SBRT. No patient had a fistula in the absence of adjuvant VEGF-modulating agents.
Esophageal fistula is a rare complication of SBRT. In this series, fistula was seen with esophageal point doses exceeding 51 Gy and 1-cc doses greater than 48 Gy. Notably, however, fistula was seen only in those patients who also received adjuvant VEGF-modulating agents after SBRT. The potential interaction of dose and adjuvant therapy should be considered when delivering SBRT near the esophagus.
BACE1 is a promising therapeutic and preventive target for Alzheimer's disease because it is essential for amyloid deposition. However, the recent demonstration of BACE1 in modulating developmental ...myelination in both peripheral and central nervous systems raises a concern of its effect on myelin maintenance or remyelination, and inhibition of these processes will potentially be detrimental to the BACE1 inhibitor users who are susceptible to myelination diseases such as adult peripheral nerve injury or multiple sclerosis. In this report, we investigated the role of BACE1 during peripheral nerve remyelination in wild-type (WT) and BACE1-null mice. We show here that genetic deletion of BACE1 affects sciatic nerve remyelination. The impaired remyelination appears to stem from the loss of neuregulin-1 cleavage by BACE1. To demonstrate a direct cleavage of neuregulin-1 by BACE1, we have identified a BACE1 cleavage site that turns out be highly conserved among neuregulin-1 paralogues. Moreover, we show that neuregulin-1 family member neuregulin-3 is also cleavable by BACE1. We hypothesize that the BACE1-cleaved extracellular domain of axonal neuregulin-1, perhaps neuregulin-3 as well, binds to Schwann cell ErbB receptors, which in turn regulate remyelination. Pharmacological inhibition of BACE1 should be carefully monitored to avoid alteration of signaling pathway that regulates remyelination.--Hu, X., He, W., Diaconu, C., Tang, X., Kidd, G. J., Macklin, W. B., Trapp, B. D., Yan, R. Genetic deletion of BACE1 in mice affects remyelination of sciatic nerves.
Disruption of the blood–brain barrier (BBB) is a defining and early feature of multiple sclerosis (MS) that directly damages the central nervous system (CNS), promotes immune cell infiltration, and ...influences clinical outcomes. There is an urgent need for new therapies to protect and restore BBB function, either by strengthening endothelial tight junctions or suppressing endothelial vesicular transcytosis. Although wingless integrated MMTV (Wnt)/β-catenin signaling plays an essential role in BBB formation and maintenance in healthy CNS, its role in BBB repair in neurologic diseases such as MS remains unclear. Using a Wnt/β-catenin reporter mouse and several downstream targets, we demonstrate that the Wnt/β-catenin pathway is up-regulated in CNS endothelial cells in both human MS and the mouse model experimental autoimmune encephalomyelitis (EAE). Increased Wnt/β-catenin activity in CNS blood vessels during EAE progression correlates with up-regulation of neuronal Wnt3 expression, as well as breakdown of endothelial cell junctions. Genetic inhibition of the Wnt/β-catenin pathway in CNS endothelium before disease onset exacerbates the clinical presentation of EAE, CD4⁺ T-cell infiltration into the CNS, and demyelination by increasing expression of vascular cell adhesion molecule-1 and the transcytosis protein Caveolin-1 and promoting endothelial transcytosis. However, Wnt signaling attenuation does not affect the progressive degradation of tight junction proteins or paracellular BBB leakage. These results suggest that reactivation of Wnt/β-catenin signaling in CNS vessels during EAE/MS partially restores functional BBB integrity and limits immune cell infiltration into the CNS.
The aim of this study was to investigate the changes caused by the administration of ketoprofen to albino NMRI mice on some hematological, biochemical, and structural parameters. For this purpose, ...the mice were divided into two lots: a control batch and an experimental batch to which ketoprofen was administered subcutaneously at a dose of 10 mg/kg body weight per day for 7 days. A decrease in erythrocyte number and hemoglobin was observed altogether with the increase in white blood cells. Blood biochemistry indicates increased blood glucose, cholesterol, and triglyceride levels. Enzyme values (AST, ALT, and ALP) show a significant increase. Hepatic pathology reveals the enlargement of sinusoidal capillaries, the presence of leukocyte infiltrates associated with necrosis zones.
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