A mechanism for tunable autoinhibition in the structure of a human Ca2+/calmodulin- dependent kinase II holoenzyme.

Calcium/calmodulin-dependent kinase II (CaMKII) forms a highly conserved dodecameric assembly that is sensitive to the frequency of calcium pulse trains. Neither the structure of the dodecameric assembly nor how it regulates CaMKII are known. We present the crystal structure of an autoinhibited full-length human CaMKII holoenzyme, revealing an unexpected compact arrangement of kinase domains docked against a central hub, with the calmodulin-binding sites completely inaccessible. We show that this compact docking is important for the autoinhibition of the kinase domains and for setting the calcium response of the holoenzyme. Comparison of CaMKII isoforms, which differ in the length of the linker between the kinase domain and the hub, demonstrates that these interactions can be strengthened or weakened by changes in linker length. This equilibrium between autoinhibited states provides a simple mechanism for tuning the calcium response without changes in either the hub or the kinase domains.

Anti-Ma2 Antibody-Mediated Paraneoplastic Cerebellar Degeneration and Myeloneuropathy Secondary to Lymphoma.

ABSTRACT: A 61-year-old woman with a history of untreated low-grade B-cell lymphoma presented with blurry vision, unsteadiness, and worsening pain on touching skin of the upper trunk was enrolled. Blurry vision was attributed to oscillopsia from downbeat nystagmus, which later evolved into macrosaccadic oscillations. MRI brain and spine showed mild, longitudinally extensive T2 hyperintensity in the central gray matter of the spinal cord extending from the medulla to T11 level. Serum paraneoplastic panel was negative; however, she had very high titers of anti-Ma2 antibodies in cerebrospinal fluid. The diagnosis of paraneoplastic neurological syndrome was made. Empiric treatment with high dose of intravenous steroids followed by intravenous immunoglobulin infusions did not improve her symptoms. An extensive search for an underlying tumor commenced and was initially unrevealing. However, two-month follow-up positron emission tomography scan showed increased uptake in a right pulmonary nodule, which when biopsied confirmed diagnosis of extranodal marginal zone lymphoma. The final diagnosis was anti-Ma2 antibody-mediated paraneoplastic cerebellar degeneration and myeloneuropathy secondary to lymphoma.

Prevalence of Venous Infarction in Patients With Cerebral Venous Thrombosis: Baseline Diffusion-Weighted MRI and Follow-Up MRI.

BACKGROUND: A venous pattern of infarction on neuroimaging is used as a clue to undiagnosed cerebral venous thrombosis (CVT); prevention of venous infarction is a goal of CVT management; and venous infarction is a factor used for clinical prognostication. Despite widespread use of the term venous infarct, the prevalence of true venous infarction is unclear. Our primary aim was to determine the prevalence of venous infarction in patients with CVT. We also measured the prevalence of diffusion abnormality without infarction, vasogenic edema, and intracranial hemorrhage. METHODS: Single-center, retrospective cohort study using a registry of 110 consecutive patients admitted to hospital with cerebral venous thrombosis between 2004 and 2014. Inclusion criteria were brain magnetic resonance imaging (MRI) and contrast-enhanced venography at presentation, and repeat brain MRI ≥1 month later. Exclusion criteria were dural arteriovenous fistula, arteriovenous malformation, cavernous sinus thrombosis, or previous neurosurgical procedure. Main outcome was proportion of patients with venous infarction (irreversible ischemic injury) diagnosed using diffusion-weighted MRI at presentation, confirmed using T2-weighted fluid-attenuated inversion recovery MRI ≥1 month later, and reported with 95% CI using the Wilson score interval method. We also report the prevalence of transient diffusion MRI abnormality without infarction, vasogenic edema, and intracranial hemorrhage. RESULTS: Seventy-three patients met the inclusion criteria, and after exclusions, the final study population was 59 patients with median age 41 years (interquartile range, 32-57). Venous infarction occurred in 12% (7/59 [95% CI, 6%-23%]) of patients, and final infarct volume was >1 mL in only 5.1% (3/59) of patients. An additional 8% (5/59 [95% CI, 4%-18%]) of patients had a transient diffusion MRI abnormality without infarction. Prevalence of cerebral vasogenic edema and intracranial hemorrhage were 66% (39/59 [95% CI, 53%-77%]) and 54% (32/59 [95% CI, 41%-66%]), respectively. CONCLUSIONS: In patients with CVT, venous infarction is uncommon and venous infarcts are typically very small. Vasogenic edema and hemorrhage are more common consequences of CVT.

Surgical left atrial appendage occlusion with concomitant cardiac surgical procedures: exacerbating heart failure or preventing stroke.

PURPOSE OF REVIEW: The left atrial appendage (LAA) is a common source of thromboembolic stroke in patients with atrial fibrillation. Current guidelines recommend consideration of surgical LAA occlusion concomitant with other cardiac surgical procedures based mostly on observational data and a few small trials. Recently published results of several large retrospective studies and one prospective trial are reviewed herein. RECENT FINDINGS: Large retrospective studies using quality and administrative databases show mixed results with regard to efficacy of surgical LAA occlusion in preventing stroke, although most showed stroke reduction in patients with a history of atrial fibrillation (AF). Safety concerns have been raised based on nonrandomized data suggesting increased complications. A recent large, multicenter international randomized study with 3-year follow-up demonstrated significant reduction in stroke following LAA occlusion with no differences in death or heart failure exacerbations. SUMMARY: Most patients with AF undergoing another cardiac surgical procedure should be considered for concomitant LAA occlusion as part of a heart team discussion. The choice of surgical closure technique is critical. There is insufficient data to recommend LAA occlusion as an alternative to anticoagulation.

An Approach to Standard Perioperative Transthoracic Echocardiography Practice for Anesthesiologists-Perioperative Transthoracic Echocardiography Protocols.

The use of intraoperative transesophageal echocardiography (TEE) has become the standard of care for most cardiac surgical procedures. There are guidelines established for training, practice, and quality improvement in perioperative TEE by the joint efforts of the American Society of Echocardiography and Society of Cardiovascular Anesthesiologists. Cardiac point-of-care ultrasound (POCUS) increasingly is being incorporated into anesthesiologists' training and practice. While a special "certification in Critical Care Echocardiography" was created by the National Board of Echocardiography in 2019, there currently exist no guidelines for training, certification, and practice of perioperative TTE by anesthesiologists. In this review, the authors describe the categories, indications and applications of perioperative TTE and provide a recommended sequence for performing an examination tailored to the evaluation of perioperative patients. Although the authors describe a protocol utilized at their institution, there are no standards described in the literature for PTTE. Cardiac anesthesiologists and cardiac anesthesia societies (Society of Cardiovascular Anesthesiologists, European Association of Cardiothoracic Anesthesiologists) must come forward to establish standards working in collaboration with echocardiography societies (American Society of Echocardiography, European Society of Cardiology).

Reversible neurological and brain MRI changes following COVID-19 vaccination: A case report.

BACKGROUND: Various neurological sequalae have been described following COVID-19 vaccination. Here we describe the first case of untreated post COVID-19 vaccine encephalitis with spontaneous resolution of contrast enhancing hyperintensities on MRI concomitant with clinical improvement. CASE PRESENTATION: A 59-year-old woman presented with a two-day history of unsteady gait, incoordination, visual symptoms, and lethargy. She had received AZD1222 (AstraZeneca) and mRNA-1273 (Moderna) COVID-19 vaccines at 3 months and 12 days, respectively, before presentation. Brain MRI showed no abnormality on the non-enhanced sequences, but numerous enhancing lesions in the cerebral cortex, deep grey matter, brainstem, and cerebellum. Treatment was expectant, the patient improved clinically over 10 days, and repeat MRI showed near complete resolution of the imaging abnormality. CONCLUSIONS: We describe neurological deterioration 12 days after a second dose of COVID-19 vaccine. There was no evidence of edema or demyelinating lesions in the brain on MRI, but there was extensive contrast-enhancement indicating loss of blood-brain barrier (BBB) integrity. This provides a potential in vivo, clinical-imaging correlate of the post-mortem evidence that SARS-CoV-2 spike protein may induce loss of BBB permeability. While this adds to the list of rare adverse neurological reactions to COVID-19 vaccination, the benefits of receiving the vaccine far outweigh these risks.

Biocontainment of genetically modified organisms by synthetic protein design.

Genetically modified organisms (GMOs) are increasingly deployed at large scales and in open environments. Genetic biocontainment strategies are needed to prevent unintended proliferation of GMOs in natural ecosystems. Existing biocontainment methods are insufficient because they impose evolutionary pressure on the organism to eject the safeguard by spontaneous mutagenesis or horizontal gene transfer, or because they can be circumvented by environmentally available compounds. Here we computationally redesign essential enzymes in the first organism possessing an altered genetic code (Escherichia coli strain C321.ΔA) to confer metabolic dependence on non-standard amino acids for survival. The resulting GMOs cannot metabolically bypass their biocontainment mechanisms using known environmental compounds, and they exhibit unprecedented resistance to evolutionary escape through mutagenesis and horizontal gene transfer. This work provides a foundation for safer GMOs that are isolated from natural ecosystems by a reliance on synthetic metabolites.

Chronic Sixth Nerve Palsy due to Compression by the Anterior Inferior Cerebellar Artery.

A 65-year-old healthy woman presented with a 15-year history of binocular horizontal diplopia worse when looking left. She had previously been thoroughly investigated multiple times for a left sixth nerve palsy (6NP) 15 years ago and had three normal magnetic resonance imaging (MRI) scans of the brain/orbits with contrast, normal acetylcholine receptor antibodies, normal thyroid function tests, normal cerebrospinal fluid, and normal nerve conduction studies and single-fibre electromyography. She was treated with prism glasses, which resulted in resolution of her symptoms in primary position.

Anatomic and Patient Risk Factors for Postoperative Periprosthetic Hip Fractures: A Case-Control Study.

BACKGROUND: Periprosthetic fracture remains a major source of reoperation following total hip arthroplasty (THA). Within 90 days of surgery, fractures may occur spontaneously or with minor injury and are therefore more likely related to patient factors including anatomic variation. METHODS: From 2008 to 2018, 16,254 primary THAs were performed at our institution; of those, 48 were revised for periprosthetic fracture within 90 days of surgery. A control group of 193 patients undergoing THA for hip osteoarthritis (OA) was randomly selected from the source population. We excluded patients with genetic bone disease and THA performed for hip fracture. We used logistic regression to analyze associations between patient factors (demographics, anatomical factors, comorbidities, surgical technique, and implants) and odds of 90-day periprosthetic fracture. RESULTS: Increased age was significantly associated with fracture (P = .002), as was female gender (P = .046). After adjusting for age and gender, absence of contralateral OA was associated with increased odds of fracture relative to patients with contralateral OA (odds ratio [OR] 3.85, 95% confidence interval [CI] 1.60-9.29), as was having a contralateral THA in place (OR 3.70, 95% CI 1.59-8.60). The neck-shaft angle, femoral offset, and the Dorr classification were not associated with increased odds of fracture. Additionally, the distance from the tip of the trochanter to the top of the femoral head was associated with increased odds of fracture per half centimeter (OR 1.48, 95% CI 1.14-1.93). CONCLUSION: Risk of early postoperative periprosthetic fracture following THA is increased with age, female gender, and increasing distance from the greater trochanter to the top of the femoral head; and decreased in the setting of contralateral hip OA. The trochanter-head distance correlation with periprosthetic hip fracture indicates that the preoperative anatomy may influence PPF, particularly regarding how that anatomy is reconstructed.

EGFR-Binding Peptides: From Computational Design towards Tumor-Targeting of Adeno-Associated Virus Capsids.

The epidermal growth factor receptor (EGFR) plays a central role in the progression of many solid tumors. We used this validated target to analyze the de novo design of EGFR-binding peptides and their application for the delivery of complex payloads via rational design of a viral vector. Peptides were computationally designed to interact with the EGFR dimerization interface. Two new peptides and a reference (EDA peptide) were chemically synthesized, and their binding ability characterized. Presentation of these peptides in each of the 60 capsid proteins of recombinant adeno-associated viruses (rAAV) via a genetic based loop insertion enabled targeting of EGFR overexpressing tumor cell lines. Furthermore, tissue distribution and tumor xenograft specificity were analyzed with systemic injection in chicken egg chorioallantoic membrane (CAM) assays. Complex correlations between the targeting of the synthetic peptides and the viral vectors to cells and in ovo were observed. Overall, these data demonstrate the potential of computational design in combination with rational capsid modification for viral vector targeting opening new avenues for viral vector delivery and specifically suicide gene therapy.

Postpartum Period Is a Risk Factor for Cerebral Venous Thrombosis.

Background and Purpose- Pregnancy and the postpartum period are generally considered to be risk factors for cerebral venous thrombosis (CVT), but no controlled studies have quantified the risk. Methods- Case-control study using data of consecutive adult patients with CVT from 5 academic hospitals and controls from the Dutch MEGA study (Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis). Men, women over the age of 50, women using oral contraceptives or with a recent abortion or miscarriage were excluded. We adjusted for age and history of cancer, and stratified for pregnancy versus postpartum, and 0 to 6 versus 7 to 12 weeks postpartum. Results- In total 163/813 cases and 1230/6296 controls were included. Cases were younger (median 38 versus 41 years) and more often had a history of cancer (14% versus 4%) than controls. In total 41/163 (25%) cases and 82/1230 (7%) controls were pregnant or postpartum (adjusted odds ratio, 3.8; 95% CI, 2.4-6.0). The association was fully attributable to an increased risk of CVT during the postpartum period (adjusted odds ratio, 10.6; 95% CI, 5.6-20.0). We found no association between pregnancy and CVT (adjusted odds ratio, 1.2; 95% CI, 0.6-2.3). The risk was highest during the first 6 weeks postpartum (adjusted odds ratio, 18.7; 95% CI, 8.3-41.9). Conclusions- Women who have recently delivered are at increased risk of developing CVT, while there does not seem to be an increased risk of CVT during pregnancy.

Cerebral Venous Thrombosis in Older Patients.

BACKGROUND AND PURPOSE: Cerebral venous thrombosis (CVT) is rare in older patients. We investigated whether clinical features and outcomes differ in older and younger patients. METHODS: We used data from a multicenter observational registry of consecutive adult patients with CVT admitted between 1987 and 2016. We compared demographics, clinical manifestations, and outcomes between older (upper quartile of the age distribution) and younger (lower 3 quartiles of the age distribution) patients. RESULTS: Data for 843 patients with CVT were available. The median age was 43 years (interquartile range, 30-55 years). Older patients (≥55 years; n=222) were less often women than younger patients (48% versus 71%; P<0.001) and less often reported headache (63% versus 87%; P<0.001). Cancer was more common in older patients (24% versus 9%; P<0.001), especially solid malignancies (19% versus 5%; P<0.001). Outcome at follow-up was worse in older patients (modified Rankin Scale, 3-6; adjusted odds ratio, 2.68; 95% confidence interval, 1.78-4.03; mortality, adjusted odds ratio, 2.13; 95% confidence interval, 1.09-4.19). CONCLUSIONS: The sex ratio of CVT is evenly distributed in older patients, probably because of the dissipation of hormonal influences. Malignancy should be considered as a potential precipitant in older patients with CVT.

Critical Illness-Associated Cerebral Microbleeds.

BACKGROUND AND PURPOSE: Cerebral microbleeds (petechial hemorrhages) are a well-known consequence of cerebral amyloid angiopathy and chronic hypertension among other causes. We report 12 patients with a clinically and radiologically distinct microbleed phenomenon in the cerebral white matter. METHODS: These patients were assessed at the University Health Network (Toronto, Canada) between 2004 and 2014. RESULTS: Median age was 40 years (range, 27-63 years), and 7 out of 12 patients were women. All patients had brain magnetic resonance imaging during or immediately after an intensive care unit admission. All patients had respiratory failure, 11 out of 12 received mechanical ventilation, and 3 out of 12 received extracorporeal life support. Magnetic resonance imaging in all 12 patients showed extensive microbleeds, diffusely involving the juxtacortical white matter and corpus callosum but sparing the cortex, deep and periventricular white matter, basal ganglia, and thalami. Several patients also had internal capsule or posterior fossa involvement. CONCLUSIONS: We have described a distinct microbleed phenomenon in the cerebral white matter of patients with critical illness. The specific cause of the microbleeds is unclear, but the pathogenesis may involve hypoxemia as the microbleeds are similar to those described with high-altitude exposure.

Development of White Matter Hyperintensity Is Preceded by Reduced Cerebrovascular Reactivity.

OBJECTIVE: White matter hyperintensities (WMH) observed on neuroimaging of elderly individuals are associated with cognitive decline and disability. However, the pathogenesis of WMH remains poorly understood. We observed that regions of reduced cerebrovascular reactivity (CVR) in the white matter of young individuals correspond to the regions most susceptible to WMH in the elderly. This finding prompted us to consider that reduced CVR may play a role in the pathogenesis of WMH. We hypothesized that reduced CVR precedes development of WMH. METHODS: We examined 45 subjects (age range = 50-91 years; 25 males) with moderate-severe WMH, and measured their baseline CVR using the blood oxygen level-dependent magnetic resonance imaging signal response to a standardized step change in the end-tidal partial pressure of carbon dioxide. Diffusion tensor imaging and transverse relaxation time (T2) relaxometry were performed at baseline and 1-year follow-up, with automated coregistration between time points. Baseline fractional anisotropy (FA), mean diffusivity (MD), T2, and CVR were measured in areas that progressed from normal-appearing white matter (NAWM) to WMH over the 1-year period. RESULTS: CVR and FA values in baseline NAWM that progressed to WMH were lower by mean (standard deviation) = 26.5% (23.2%) and 11.0% (7.2%), respectively, compared to the contralateral homologous NAWM that did not progress (p < 0.001). T2 and MD were higher by 8.7% (7.9%) and 17.0% (8.5%), respectively, compared to the contralateral homologous NAWM (p < 0.001). INTERPRETATION: Areas of reduced CVR precede the progression from NAWM to WMH, suggesting that hemodynamic impairment may contribute to the pathogenesis and progression of age-related white matter disease. Ann Neurol 2016;80:277-285.

Natural history of lesions with the MR imaging appearance of multinodular and vacuolating neuronal tumor.

PURPOSE: Multinodular and vacuolating neuronal tumor (MVNT) have been recently added to the WHO classification of CNS tumors and has not been extensively reported upon in the radiological literature. We report the first radiological and the largest series of cases, aiming to highlight the natural history of lesions with the imaging appearance of MVNT with long follow-up time. METHODS: In this retrospective study, we collected cases with the imaging appearance of MVNT. All lesions were evaluated by using routine MR imaging, with follow-up of up to 93 months. Patient demographics, clinical course, and MRI features of the lesions were recorded. RESULTS: Twenty-four subjects were enrolled, f/m = 16:8, age range 24-59 years, with a median age of 45 years. The patients' symptoms were often episodic and most frequently due to headaches in 12 (50%), visual symptoms in 6 (25%), seizures in 5 ± 1 (20-25%), paresthesia in 4 (~17%), cognitive difficulties in 4 (~17%), in addition to other variable neurological symptoms, or incidental. A total of 30 lesions identified, 77% of the lesions had gadolinium-enhanced MRI and only 13% showed enhancement. A 6.7% of the lesions that had MRI followed up showed progression, while the rest remained stable up to 93 months interval. All patients had intact neurological examinations (except one case that was diagnosed with optic neuritis), were managed conservatively, and did well. CONCLUSION: The natural history of lesions with imaging features of MVNT is overall stable from a clinical and imaging appearance over time.