Publications by authors named "Steven Jacobson"

195 Publications

Human Herpes Virus 6 and Epilepsy.

Epilepsia Open 2021 Jul 29. Epub 2021 Jul 29.

Division of Intramural Research, National Institute of Neurological, Disorders and Stroke (1), Bethesda, MD, USA.

We investigated the association between human herpes virus 6 (HHV-6) and mesial temporal sclerosis (MTS) in 87 patients who had surgery for drug-resistant epilepsy. Fifty-four had MTS, 22 focal cortical dysplasia (FCD), four tumors, three vascular malformations and three a history of encephalitis. We extracted DNA from fresh brain tissue immediately after surgery and performed viral detection with quantitative real time polymerase chain reaction (PCR) or digital droplet PCR specific for HHV-6A and HHV-6B. Tissue was studied with standard clinical techniques, including hematoxylin and eosin, glial fibrillary acidic protein and NeuN stains. Twenty-nine of 54 patients with MTS, six of 23 with focal cortical dysplasia (FCD), and one of three with a history of encephalitis were positive for HHV6 (p <0.02). Febrile seizure history was not associated with HHV6 detection. Patients with MTS had significantly lower seizure onset age than those with other pathologies. Thirteen patients had positron emission tomography with [11C]PBR28, a marker for reactive astrocytes and activated microglia; there was a trend for HHV-6 positive patients to have higher binding in their seizure foci, suggesting inflammation. Our study supports a potential role for HHV-6 in the etiology of MTS.
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http://dx.doi.org/10.1002/epi4.12531DOI Listing
July 2021

BK virus-specific T cells for immunotherapy of progressive multifocal leukoencephalopathy: an open-label, single-cohort pilot study.

Lancet Neurol 2021 Aug;20(8):639-652

Hematology Branch, Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA.

Background: Progressive multifocal leukoencephalopathy, a rare disease of the CNS caused by JC virus and occurring in immunosuppressed people, is typically fatal unless adaptive immunity is restored. JC virus is a member of the human polyomavirus family and is closely related to the BK virus. We hypothesised that use of partly HLA-matched donor-derived BK virus-specific T cells for immunotherapy in progressive multifocal leukoencephalopathy would be feasible and safe.

Methods: We did an open-label, single-cohort pilot study in patients (aged 18 years or older) with clinically definite progressive multifocal leukoencephalopathy and disease progression in the previous month at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD, USA). Overlapping peptide libraries derived from large T antigen and major capsid protein VP1 of BK virus with high sequence homology to JC virus counterparts were used to generate polyomavirus-specific T cells cross-recognising JC virus antigens. Polyomavirus-specific T cells were manufactured from peripheral blood mononuclear cells of first-degree relative donors aged 18 years or older. These cells were administered to patients by intravenous infusion at 1 × 10 polyomavirus-specific T cells per kg, followed by up to two additional infusions at 2 × 10 polyomavirus-specific T cells per kg. The primary endpoints were feasibility (no manufacturing failure based on meeting release criteria, achieving adequate numbers of cell product for clinical use, and showing measurable antiviral activity) and safety in all patients. The safety monitoring period was 28 days after each infusion. Patients were followed up with serial MRI for up to 12 months after the final infusion. This trial is registered at ClinicalTrials.gov, NCT02694783.

Findings: Between April 7, 2016, and Oct 19, 2018, 26 patients were screened, of whom 12 were confirmed eligible and received treatment derived from 14 matched donors. All administered polyomavirus-specific T cells met the release criteria and recognised cognate antigens in vitro. 12 patients received at least one infusion, ten received at least two, and seven received a total of three infusions. The median on-study follow-up was 109·5 days (range 23-699). All infusions were tolerated well, and no serious treatment-related adverse events were observed. Seven patients survived progressive multifocal leukoencephalopathy for longer than 1 year after the first infusion, whereas five died of progressive multifocal leukoencephalopathy within 3 months.

Interpretation: We showed that generation of polyomavirus-specific T cells from healthy related donors is feasible, and these cells can be safely used as an infusion for adoptive immunotherapy of progressive multifocal leukoencephalopathy. Although not powered to assess efficacy, our data provide additional support for this strategy as a potential life-saving therapy for some patients.

Funding: Intramural Research Program of the National Institute of Neurological Disorders and Stroke of the NIH.
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http://dx.doi.org/10.1016/S1474-4422(21)00174-5DOI Listing
August 2021

Cervical and thoracic cord atrophy in multiple sclerosis phenotypes: Quantification and correlation with clinical disability.

Neuroimage Clin 2021 28;30:102680. Epub 2021 Apr 28.

Viral Immunology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States. Electronic address:

Objective: We sought to characterize spinal cord atrophy along the entire spinal cord in the major multiple sclerosis (MS) phenotypes, and evaluate its correlation with clinical disability.

Methods: Axial T-weighted images were automatically reformatted at each point along the cord. Spinal cord cross-sectional area (SCCSA) were calculated from C1-T10 vertebral body levels and profile plots were compared across phenotypes. Average values from C2-3, C4-5, and T4-9 regions were compared across phenotypes and correlated with clinical scores, and then categorized as atrophic/normal based on z-scores derived from controls, to compare clinical scores between subgroups. In a subset of relapsing-remitting cases with longitudinal scans these regions were compared to change in clinical scores.

Results: The cross-sectional study consisted of 149 adults diagnosed with relapsing-remitting MS (RRMS), 49 with secondary-progressive MS (SPMS), 58 with primary-progressive MS (PPMS) and 48 controls. The longitudinal study included 78 RRMS cases. Compared to controls, all MS groups had smaller average regions except RRMS in T4-9 region. In all MS groups, SCCSA from all regions, particularly the cervical cord, correlated with most clinical measures. In the RRMS cohort, 22% of cases had at least one atrophic region, whereas in progressive MS the rate was almost 70%. Longitudinal analysis showed correlation between clinical disability and cervical cord thinning.

Conclusions: Spinal cord atrophy was prevalent across MS phenotypes, with regional measures from the RRMS cohort and the progressive cohort, including SPMS and PPMS, being correlated with disability. Longitudinal changes in the spinal cord were documented in RRMS cases, making it a potential marker for disease progression. While cervical SCCSA correlated with most disability and progression measures, inclusion of thoracic measurements improved this correlation and allowed for better subgrouping of spinal cord phenotypes. Cord atrophy is an important and easily obtainable imaging marker of clinical and sub-clinical progression in all MS phenotypes, and such measures can play a key role in patient selection for clinical trials.
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http://dx.doi.org/10.1016/j.nicl.2021.102680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131917PMC
July 2021

Differential activation of neuroinflammatory pathways in children with seizures: A cross-sectional study.

Seizure 2021 May 31;91:150-158. Epub 2021 May 31.

Division of Neuroimmunology and Neurovirology, NINDS, NIH, Bethesda, MD, United States.

Purpose: Inflammation plays a crucial role in epileptogenesis. We analyzed inflammatory cytokines in plasma and saliva from children with seizures and healthy controls and measured their associations with HHV6 and EBV infection.

Methods: We analyzed plasma from 36 children within 24 h of seizures (cases) and 43 healthy controls and saliva from 44 cases and 44 controls with a multiplex immunoassay. Saliva from all controls and 65 cases and blood from 26 controls and 35 cases were also analyzed by PCR for viral DNA. Primary outcome was cytokine levels in cases vs. controls. Secondary outcomes included detection of HHV-6 and EBV viral DNA in cases vs. controls and viral loads in cases vs. controls. Statistical analysis included the Wilcoxon Rank Sum test, Fisher's exact test, ANOVA, and Spearman correlation.

Results: Compared to controls, patients had higher levels of CCL11 (p = 0.0018), CCL26 (p<0.001), IL10 (p = 0.044), IL6 (p<0.001), IL8 (p = 0.018), and MIP1β (p = 0.0012). CCL11 was higher with 3 or more seizures (p = 0.01), seizures longer than 10 min (p = 0.001), and when EEG showed focal slowing (p = 0.02). In saliva, febrile seizures had higher levels of IL-1β (n = 7, p = 0.04) and new onset seizures had higher IL-6 (n = 15, p = 0.02). Plasma and saliva cytokine levels did not show a correlation. The frequency of HHV-6 and EBV detection was similar across groups and not different than controls. We found no correlation between viral load and cytokine levels.

Conclusions: We showed differential activation of neuroinflammatory pathways in plasma from different seizure etiologies compared to controls, unrelated to viral infection.
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http://dx.doi.org/10.1016/j.seizure.2021.05.022DOI Listing
May 2021

Effect of Teriflunomide on Cells From Patients With Human T-cell Lymphotropic Virus Type 1-Associated Neurologic Disease.

Neurol Neuroimmunol Neuroinflamm 2021 05 9;8(3). Epub 2021 Apr 9.

From the Viral Immunology Section (Y.E.-A., N.N., S.J.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD; Joan Ohayon, Neuroimmunology Clinic (J.O.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD; and Sanofi (M.M., J.C., T.J.T.), Cambridge, MA.

Objective: To test the hypothesis that teriflunomide can reduce ex vivo spontaneous proliferation of peripheral blood mononuclear cells (PBMCs) from patients with human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP).

Methods: PBMCs from patients with HAM/TSP were cultured in the presence and absence of teriflunomide and assessed for cell viability, lymphocyte proliferation, activation markers, HTLV-1 and HTLV-1 messenger ribonucleic acid (mRNA) expression, and HTLV-1 Tax protein expression.

Results: In culture, teriflunomide did not affect cell viability. A concentration-dependent reduction in spontaneous proliferation of PBMCs was observed with 25 μM (38.3% inhibition), 50 μM (65.8% inhibition), and 100 μM (90.7% inhibition) teriflunomide. The inhibitory effects of teriflunomide were detected in both CD8 and CD4 T-cell subsets, which are involved in the immune response to HTLV-1 infection and the pathogenesis of HAM/TSP. There was no significant change in HTLV-1 proviral load (PVL) or mRNA/Tax protein expression in these short-term cultures, but there was a significant reduction of HTLV-1 PVL due to inhibition of proliferation of CD4 T cells obtained from a subset of patients with HAM/TSP.

Conclusions: These results suggest that teriflunomide inhibits abnormal T-cell proliferation associated with HTLV-1 infection and may have potential as a therapeutic option in patients with HAM/TSP.
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http://dx.doi.org/10.1212/NXI.0000000000000986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054963PMC
May 2021

Immunopathogenic CSF TCR repertoire signatures in virus-associated neurologic disease.

JCI Insight 2021 Feb 22;6(4). Epub 2021 Feb 22.

Viral Immunology Section, Neuroimmunology Branch and.

In this study, we examined and characterized disease-specific TCR signatures in cerebrospinal fluid (CSF) of patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). TCR β libraries using unique molecular identifier-based methodologies were sequenced in paired peripheral blood mononuclear cells (PBMCs) and CSF cells from HAM/TSP patients and normal healthy donors (NDs). The sequence analysis demonstrated that TCR β repertoires in CSF of HAM/TSP patients were highly expanded and contained both TCR clonotypes shared with PBMCs and uniquely enriched within the CSF. In addition, we analyzed TCR β repertoires of highly expanded and potentially immunopathologic HTLV-1 Tax11-19-specific CD8+ T cells from PBMCs of HLA-A*0201+ HAM/TSP and identified a conserved motif (PGLAG) in the CDR3 region. Importantly, TCR β clonotypes of expanded clones in HTLV-1 Tax11-19-specific CD8+ T cells were also expanded and enriched in the CSF of the same patient. These results suggest that exploring TCR repertoires of CSF and antigen-specific T cells may provide a TCR repertoire signature in virus-associated neurologic disorders.
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http://dx.doi.org/10.1172/jci.insight.144869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934934PMC
February 2021

Progressive multifocal leukoencephalopathy lesion and brain parenchymal segmentation from MRI using serial deep convolutional neural networks.

Neuroimage Clin 2020 11;28:102499. Epub 2020 Nov 11.

Neuroimmunology Clinic, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA. Electronic address:

Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic brain infection caused by the JC virus and associated with substantial morbidity and mortality. Accurate MRI assessment of PML lesion burden and brain parenchymal atrophy is of decisive value in monitoring the disease course and response to therapy. However, there are currently no validated automatic methods for quantification of PML lesion burden or associated parenchymal volume loss. Furthermore, manual brain or lesion delineations can be tedious, require the use of valuable time resources by radiologists or trained experts, and are often subjective. In this work, we introduce JCnet (named after the causative viral agent), an end-to-end, fully automated method for brain parenchymal and lesion segmentation in PML using consecutive 3D patch-based convolutional neural networks. The network architecture consists of multi-view feature pyramid networks with hierarchical residual learning blocks containing embedded batch normalization and nonlinear activation functions. The feature maps across the bottom-up and top-down pathways of the feature pyramids are merged, and an output probability membership generated through convolutional pathways, thus rendering the method fully convolutional. Our results show that this approach outperforms and improves longitudinal consistency compared to conventional, state-of-the-art methods of healthy brain and multiple sclerosis lesion segmentation, utilized here as comparators given the lack of available methods validated for use in PML. The ability to produce robust and accurate automated measures of brain atrophy and lesion segmentation in PML is not only valuable clinically but holds promise toward including standardized quantitative MRI measures in clinical trials of targeted therapies. Code is available at: https://github.com/omarallouz/JCnet.
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http://dx.doi.org/10.1016/j.nicl.2020.102499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708929PMC
June 2021

HHV-6 and hippocampal volume in patients with mesial temporal sclerosis.

Ann Clin Transl Neurol 2020 09 17;7(9):1674-1680. Epub 2020 Aug 17.

Clinical Epilepsy Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland.

Objective: To study the effects of human herpes virus 6 (HHV-6) on the hippocampal volume in patients with mesial temporal sclerosis (MTS).

Background: HHV-6 may play an etiologic role in MTS. Previous studies found a possible association with febrile status epilepticus. Several investigators have reported a higher prevalence of HHV-6 in MTS resections compared to other epilepsy etiologies.

Design/methods: We used FreeSurfer to segment cortical structures and obtain whole hippocampal and subfield volumes in 41 patients with intractable epilepsy. In addition, an investigator blinded to other data traced hippocampi manually on each slice. The main study outcome measure was the asymmetry index (AI) between hippocampal volumes ipsilateral and contralateral to seizure foci compared between HHV-6 positive and negative patients. Viral DNA was isolated from fresh brain tissue obtained at temporal lobectomy. For 25 patients, viral detection was performed using quantitative real-time PCR specific for HHV-6A and HHV-6B. For 16 patients, viral DNA detection was performed using digital droplet PCR specific for HHV-6A and HHV-6B.

Results: Twenty-two patients were positive (14 of 25 tested with real-time PCR, and 8 of 16 with digital droplet PCR), and 19 negatives for HHV-6. HHV-6 negative patients had significantly greater AI and lower total hippocampal volume ipsilateral to seizure foci than HHV-6 positive patients. Epilepsy duration and age of onset did not affect results.

Interpretation: Our data suggest multiple potential etiologies for MTS. HHV-6 may have a less severe effect on the hippocampus than other etiologies.
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http://dx.doi.org/10.1002/acn3.51152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480901PMC
September 2020

Human Herpesviruses 6A and 6B in Brain Diseases: Association versus Causation.

Clin Microbiol Rev 2020 12 11;34(1). Epub 2020 Nov 11.

Virology/Immunology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.

Human herpesvirus 6A (HHV-6A) and human herpesvirus 6B (HHV-6B), collectively termed HHV-6A/B, are neurotropic viruses that permanently infect most humans from an early age. Although most people infected with these viruses appear to suffer no ill effects, the viruses are a well-established cause of encephalitis in immunocompromised patients. In this review, we summarize the evidence that the viruses may also be one trigger for febrile seizures (including febrile status epilepticus) in immunocompetent infants and children, mesial temporal lobe epilepsy, multiple sclerosis (MS), and, possibly, Alzheimer's disease. We propose criteria for linking ubiquitous infectious agents capable of producing lifelong infection to any neurologic disease, and then we examine to what extent these criteria have been met for these viruses and these diseases.
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http://dx.doi.org/10.1128/CMR.00143-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667666PMC
December 2020

Opinion and Special Articles: Cerebellar Ataxia and Liver Failure Complicating IPEX Syndrome.

Neurology 2021 02 9;96(6):e956-e959. Epub 2020 Nov 9.

From the Cleveland Clinic Foundation (J.R.), Neurological Institute, OH; SUNY Upstate Medical University Genetics Section (M.B., R.R.L.), Syracuse, NY; National Institute of Neurological Disorders and Stroke (NINDS) (A.S., E.L., S.J.), Bethesda; National Institute of Allergy and Infectious Diseases (NIAID) (L.N.), Bethesda, MD; Boston Children's Hospital (M.G.), Pediatric MS and Related Disorders and Neuro-immunology, MA; and Duke University (K.W.), Department of Pediatrics, Durham, NC.

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http://dx.doi.org/10.1212/WNL.0000000000011195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105902PMC
February 2021

Haploinsufficiency of immune checkpoint receptor CTLA4 induces a distinct neuroinflammatory disorder.

J Clin Invest 2020 10;130(10):5551-5561

Immunopathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease (NIAID), NIH, Bethesda, Maryland, USA.

BACKGROUNDCytotoxic T lymphocyte antigen 4 (CTLA4) is essential for immune homeostasis. Genetic mutations causing haploinsufficiency (CTLA4h) lead to a phenotypically heterogenous, immune-mediated disease that can include neuroinflammation. The neurological manifestations of CTLA4h are poorly characterized.METHODSWe performed an observational natural history study of 50 patients with CTLA4h who were followed at the NIH. We analyzed clinical, radiological, immunological, and histopathological data.RESULTSEvidence for neuroinflammation was observed in 32% (n = 16 of 50) of patients in this cohort by magnetic resonance imaging (MRI) and/or by cerebrospinal fluid analysis. Clinical symptoms were commonly absent or mild in severity, with headaches as the leading complaint (n = 13 of 16). The most striking findings were relapsing, large, contrast-enhancing focal lesions in the brain and spinal cord observed on MRI. We detected inflammation in the cerebrospinal fluid and leptomeninges before the parenchyma. Brain biopsies of inflammatory lesions from 10 patients showed perivascular and intraparenchymal mixed cellular infiltrates with little accompanying demyelination or neuronal injury.CONCLUSIONSNeuroinflammation due to CTLA4h is mediated primarily by an infiltrative process with a distinct and striking dissociation between clinical symptoms and radiological findings in the majority of patients.FUNDINGNIAID, NIH, Division of Intramural Research, NINDS, NIH, Division of Intramural Research, and the National Multiple Sclerosis Society-American Brain Foundation.TRIAL REGISTRATIONClinicalTrials.gov NCT00001355.
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http://dx.doi.org/10.1172/JCI135947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524497PMC
October 2020

Ultrahigh-resolution MRI Reveals Extensive Cortical Demyelination in a Nonhuman Primate Model of Multiple Sclerosis.

Cereb Cortex 2021 Jan;31(1):439-447

Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.

Cortical lesions are a primary driver of disability in multiple sclerosis (MS). However, noninvasive detection of cortical lesions with in vivo magnetic resonance imaging (MRI) remains challenging. Experimental autoimmune encephalomyelitis (EAE) in the common marmoset is a relevant animal model of MS for investigating the pathophysiological mechanisms leading to brain damage. This study aimed to characterize cortical lesions in marmosets with EAE using ultrahigh-field (7 T) MRI and histological analysis. Tissue preparation was optimized to enable the acquisition of high-spatial resolution (50-μm isotropic) T2*-weighted images. A total of 14 animals were scanned in this study, and 70% of the diseased animals presented at least one cortical lesion on postmortem imaging. Cortical lesions identified on MRI were verified with myelin proteolipid protein immunostaining. An optimized T2*-weighted sequence was developed for in vivo imaging and shown to capture 65% of cortical lesions detected postmortem. Immunostaining confirmed extensive demyelination with preserved neuronal somata in several cortical areas of EAE animals. Overall, this study demonstrates the relevance and feasibility of the marmoset EAE model to study cortical lesions, among the most important yet least understood features of MS.
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http://dx.doi.org/10.1093/cercor/bhaa235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947170PMC
January 2021

Paramagnetic Rim Lesions are Specific to Multiple Sclerosis: An International Multicenter 3T MRI Study.

Ann Neurol 2020 11 9;88(5):1034-1042. Epub 2020 Sep 9.

Department of Neurology, Johns Hopkins University, Baltimore, MD.

In multiple sclerosis (MS), a subset of chronic active white matter lesions are identifiable on magnetic resonance imaging by their paramagnetic rims, and increasing evidence supports their association with severity of clinical disease. We studied their potential role in differential diagnosis, screening an international multicenter clinical research-based sample of 438 individuals affected by different neurological conditions (MS, other inflammatory, infectious, and non-inflammatory conditions). Paramagnetic rim lesions, rare in other neurological conditions (52% of MS vs 7% of non-MS cases), yielded high specificity (93%) in differentiating MS from non-MS. Future prospective multicenter studies should validate their role as a diagnostic biomarker. ANN NEUROL 2020;88:1034-1042.
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http://dx.doi.org/10.1002/ana.25877DOI Listing
November 2020

Intravenous Tranexamic Acid in Implant-Based Breast Reconstruction Safely Reduces Hematoma without Thromboembolic Events.

Plast Reconstr Surg 2020 08;146(2):238-245

From the Division of Plastic Surgery, Department of Surgery, Mayo Clinic College of Medicine and Science.

Background: Antifibrinolytic medications, such as tranexamic acid, have recently garnered increased attention. Despite its ability to mitigate intraoperative blood loss and need for blood transfusion, there remains a paucity of research in breast reconstruction. The authors investigate whether intravenous tranexamic acid safely reduces the risk of hematoma following implant-based breast reconstruction.

Methods: A single-center retrospective cohort study was performed to analyze all consecutive patients undergoing immediate two-stage implant-based breast reconstruction following mastectomy between 2015 and 2016. The incidence of postoperative hematomas and thromboembolic events among all patients was reviewed. The patients in the intervention group received 1000 mg of intravenous tranexamic acid before mastectomy incision and 1000 mg at the conclusion of the procedure. Fisher's exact test and the Mann-Whitney-Wilcoxon test were used. Multivariate logistic regression models were performed to study the impact of intravenous tranexamic acid after adjusting for possible confounders.

Results: A total of 868 consecutive breast reconstructions (499 women) were reviewed. Overall, 116 patients (217 breasts) received intravenous tranexamic acid, whereas 383 patients (651 breasts) did not. Patient characteristics and comorbidities were similar between the two the groups. Patients who received tranexamic acid were less likely to develop hematomas [n = 1 (0.46 percent)] than patients who did not [n = 19 (2.9 percent)] after controlling for age, hypertension, and type of reconstruction (prepectoral and subpectoral) (p = 0.018). Adverse effects of intravenous tranexamic acid, including thromboembolic phenomena were not observed. Multivariate analysis demonstrated that age and hypertension independently increase risk for hematoma.

Conclusions: Intravenous tranexamic acid safely reduces risk of hematoma in implant-based breast reconstruction. Further prospective randomized studies are warranted to further corroborate these findings.

Clinical Question/level Of Evidence: Therapeutic, III.
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http://dx.doi.org/10.1097/PRS.0000000000006967DOI Listing
August 2020

Human T-lymphotropic virus type 1 (HTLV-1) and cellular immune response in HTLV-1-associated myelopathy/tropical spastic paraparesis.

J Neurovirol 2020 10 23;26(5):652-663. Epub 2020 Jul 23.

Viral Immunology Section, Division of Neuroimmunology and Neurovirology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.

Human T-lymphotropic virus type 1 (HTLV-1) is associated with adult T cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is an inflammatory disease of the spinal cord and clinically characterized by progressive spastic paraparesis, urinary incontinence, and mild sensory disturbance. The interaction between the host immune response and HTLV-1-infected cells regulates the development of HAM/TSP. HTLV-1 preferentially infects CD4 T cells and is maintained by proliferation of the infected T cells. HTLV-1-infected cells rarely express viral antigens in vivo; however, they easily express the antigens after short-term culture. Therefore, such virus-expressing cells may lead to activation and expansion of antigen-specific T cell responses. Infected T cells with HTLV-1 and HTLV-1-specific CD8 cytotoxic T lymphocytes invade the central nervous system and produce various proinflammatory cytokines and chemokines, leading to neuronal damage and degeneration. Therefore, cellular immune responses to HTLV-1 have been considered to play important roles in disease development of HAM/TSP. Recent studies have clarified the viral strategy for persistence in the host through genetic and epigenetic changes by HTLV-1 and host immune responses including T cell function and differentiation. Newly developed animal models could provide the opportunity to uncover the precise pathogenesis and development of clinically effective treatment. Several molecular target drugs are undergoing clinical trials with promising efficacy. In this review, we summarize recent advances in the immunopathogenesis of HAM/TSP and discuss the perspectives of the research on this disease.
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http://dx.doi.org/10.1007/s13365-020-00881-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532128PMC
October 2020

Creation and validation of a bladder dysfunction symptom score for HTLV-1-associated myelopathy/tropical spastic paraparesis.

Orphanet J Rare Dis 2020 07 3;15(1):175. Epub 2020 Jul 3.

Department of Rare Diseases Research, Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Japan.

Background: Urinary dysfunction is one of the main features of human T-cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, a comprehensive assessment of the severity is difficult because a standardized assessment measure is unavailable. Therefore, this study aimed to develop a novel symptom score for the assessment of urinary dysfunction in HAM/TSP. We interviewed 449 patients with HAM/TSP using four internationally validated questionnaires for assessment of urinary symptoms (27 question items in total): the International Prostate Symptom Score; the International Consultation on Incontinence Questionnaire-Short Form; the Overactive Bladder Symptom Score; and the Nocturia Quality-of-Life questionnaire. We developed a symptom score based on the data of 322 patients who did not use urinary catheters by selecting question items from questionnaires focused on descriptive statistics, correlation analysis, and exploratory factor analysis. The score distribution, reliability, and validity of the developed score were evaluated.

Results: First, 16 questions related to quality of life, situations, or subjective assessment were omitted from the 27 questions. Exploratory factor analysis revealed that the remaining 11 questions pertained to three factors: frequent urination, urinary incontinence, and voiding symptoms. Three questions, which had similar questions with larger factor loading, were deleted. Finally, we selected eight question items for inclusion in the novel score. The score distribution exhibited no ceiling or floor effect. The Cronbach's alpha (0.737) demonstrated reliable internal consistency. The new score comprised two subscales with acceptable factorial validity (inter-factor correlation coefficient, 0.322): storage symptoms (frequent urination plus urinary incontinence) and voiding symptoms. The correlation between each item and the subscales suggested acceptable construct validity.

Conclusions: We developed a novel score, the HAM/TSP-Bladder Dysfunction Symptom Score, and demonstrated its reliability and validity. The applicability of this score to patients using catheters should be examined in future research.
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http://dx.doi.org/10.1186/s13023-020-01451-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333329PMC
July 2020

Human Herpesvirus 6 Detection in Alzheimer's Disease Cases and Controls across Multiple Cohorts.

Neuron 2020 03 23;105(6):1027-1035.e2. Epub 2020 Jan 23.

Viral Immunology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA. Electronic address:

The interplay between viral infection and Alzheimer's disease (AD) has long been an area of interest, but proving causality has been elusive. Several recent studies have renewed the debate concerning the role of herpesviruses, and human herpesvirus 6 (HHV-6) in particular, in AD. We screened for HHV-6 detection across three independent AD brain repositories using (1) RNA sequencing (RNA-seq) datasets and (2) DNA samples extracted from AD and non-AD control brains. The RNA-seq data were screened for pathogens against taxon references from over 25,000 microbes, including 118 human viruses, whereas DNA samples were probed for PCR reactivity to HHV-6A and HHV-6B. HHV-6 demonstrated little specificity to AD brains over controls by either method, whereas other viruses, such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV), were detected at comparable levels. These direct methods of viral detection do not suggest an association between HHV-6 and AD.
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http://dx.doi.org/10.1016/j.neuron.2019.12.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182308PMC
March 2020

Immunovirological markers in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP).

Retrovirology 2019 11 29;16(1):35. Epub 2019 Nov 29.

Viral Immunology Section, National Institute of Neurological, Disorders and Stroke, National Institutes of Health, 9000 Rockville Pike, Building 10 Room 5C-103, Bethesda, MD, USA.

Human T cell lymphotropic virus 1 (HTLV-1) is a human retrovirus and infects approximately 10-20 million people worldwide. While the majority of infected people are asymptomatic carriers of HTLV-1, only 4% of infected people develop HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is a chronic, progressive, neurological disease which usually progresses slowly without remission, and is characterized by perivascular inflammatory infiltrates in chronic inflammatory lesions of the central nervous system (CNS), primarily affecting the spinal cord. A high HTLV-1 proviral load, high levels of antibodies against HTLV-1 antigens, and elevated concentration of proteins are detected in cerebrospinal fluid (CSF) of HAM/TSP patients. These chronically activated immune responses against HTLV-1 and infiltration of inflammatory cells including HTLV-1 infected cells into the CNS contribute to clinical disability and underlie the pathogenesis of HAM/TSP. Since the disease development of HAM/TSP mainly occurs in adults, with a mean age at onset of 40-50 years, it is important for HTLV-1-infected carriers and HAM/TSP patients to be monitored throughout the disease process. Recent advances in technologies and findings provide new insights to virological and immunological aspects in both the CNS as well as in peripheral blood. In this review, we focus on understanding the inflammatory milieu in the CNS and discuss the immunopathogenic process in HTLV-1-associated neurologic diseases.
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http://dx.doi.org/10.1186/s12977-019-0499-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884770PMC
November 2019

Infections following Immediate Implant-Based Breast Reconstruction: A Case-Control Study over 11 Years.

Plast Reconstr Surg 2019 12;144(6):1270-1277

From the Division of Plastic Surgery, the Division of Breast, Endocrine, Metabolic, and Gastrointestinal Surgery, Department of Surgery, the Division of Biomedical Statistics and Informatics, and the Division of Infectious Diseases, Department of Medicine, Mayo Clinic; Plastic Surgery Consultants; Jacobson Plastic Surgery; and Department of Plastic and Reconstructive Surgery, Jeonbuk National University Hospital.

Background: Surgical-site infection after implant-based breast reconstruction adversely affects surgical outcomes and increases health care costs. This 11-year case-control study examines risk factors specific for surgical-site infection after immediate tissue expander/implant-based breast reconstruction.

Methods: The authors performed a retrospective review to identify all consecutive patients with breast implant infections between 2006 and 2016. Patients who developed surgical-site infection after immediate tissue expander/implant-based breast reconstruction were included. Surgical-site infection was defined using the Centers for Disease Control and Prevention criteria; specifically, infections requiring hospital admission, intravenous antibiotics, or surgical intervention were included. The authors matched a control patient to each infection case by patient age and date of surgery. Patient demographics, medical comorbidities, and perioperative surgical variables were examined. Univariate and multivariable conditional logistic regression models were constructed.

Results: A total of 270 breasts in 252 patients were evaluated. On multivariate analysis, patients with a higher body mass index (OR, 1.1 per 1 body mass index point increase; 95 percent CI, 1.0 to 1.2; p = 0.02), hypertension (OR, 6.5; 95 percent CI, 1.9 to 22.3; p = 0.002), neoadjuvant chemotherapy (OR, 2.6; 95 percent CI, 1.0 to 6.3; p = 0.04), axillary lymph node dissection (OR, 7.1; 95 percent CI, 1.7 to 29.2; p = 0.006), seroma formation (OR, 15.34; 95 percent CI, 3.7 to 62.5; p = 0.0001), and wound healing complications (OR, 23.91; 95 percent CI, 6.1 to 93.4; p < 0.0001) were significantly associated with surgical-site infection.

Conclusions: Women with obesity, women with hypertension, and those treated with neoadjuvant chemotherapy are at increased risk of surgical-site infection. Further risks are also associated with postoperative seroma and wound complications. This may help patient selection and counseling, adjusted based on risk factors regarding complications of immediate implant-based breast reconstruction.

Clinical Question/level Of Evidence: Risk, III.
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http://dx.doi.org/10.1097/PRS.0000000000006202DOI Listing
December 2019

An evaluation of HHV-6 as an etiologic agent in Hodgkin lymphoma and brain cancer using IARC criteria for oncogenicity.

Infect Agent Cancer 2019 5;14:31. Epub 2019 Nov 5.

3College of Public Health, University of Nebraska, 984355 Medical Center, Omaha, NE 68198 USA.

Background: Human herpesvirus-6 (HHV-6) is a ubiquitous double-stranded DNA virus that can cause roseola infantum, encephalitis, and seizure disorders. Several studies have shown an association between HHV-6 and cancer but confirmation of an etiologic role is lacking. We reviewed the criteria for viral causation of cancer used by The International Agency for Research on Cancer (IARC) for six oncogenic viruses and applied criteria to published reports of HHV-6 and its association with Hodgkin lymphoma and brain tumors.

Methods: Our major criteria for oncogenicity were finding evidence of the virus in every tumor cell and prevention of the tumor by an antiviral vaccine. Our six minor criteria included: 1) suggestive serologic correlation, such as higher virus antibody levels in cases compared to controls; 2) evidence of the virus in some but not all tumor cells, and 3) time space clustering. We focused on Epstein-Barr virus (EBV) as the primary virus for comparison as HHV-6 and EBV are both Herpesviridae, ubiquitous infections, and EBV is well-accepted as a human oncovirus. Particular attention was given to Hodgkin lymphoma (HL) and brain cancer as these malignancies have been the most studied.

Results: No studies reported HHV-6 satisfying either of the major criteria for oncogenicity. Of the minor criteria used by IARC, serologic studies have been paramount in supporting EBV as an oncogenic agent in all EBV-associated tumors, but not for HHV-6 in HL or brain cancer. Clustering of cases was suggestive for both HL and brain cancer and medical intervention suggested by longer survival in patients treated with antiviral agents was reported for brain cancer.

Conclusion: There is insufficient evidence to indicate HHV-6 is an etiologic agent with respect to HL and brain cancers. We suggest that methods demonstrating EBV oncogenicity be applied to HHV-6. It is important that one study has found HHV-6 in all cancer cells in oral cancer in a region with elevated HHV-6 antibodies and therefore HHV-6 can still be considered a possible human oncogenic virus.
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http://dx.doi.org/10.1186/s13027-019-0248-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6833260PMC
November 2019

Single-Stage Direct-to-Implant Breast Reconstruction: A Comparison Between Subpectoral Versus Prepectoral Implant Placement.

Ann Plast Surg 2020 04;84(4):361-365

Division of Breast, Endocrine, Metabolic and GI Surgery, Department of Surgery, Mayo Clinic College of Medicine and Science, Rochester, MN.

Background: Single-stage direct-to-implant (DTI) breast reconstruction can offer several potential benefits. Subpectoral DTI reconstruction can present with animation deformity and pectoralis muscle spasm. To potentially avoid these complications, surgeons have attempted prepectoral placement for DTI; however, the benefits of this approach are mostly unknown. We evaluated the outcomes of DTI between prepectoral and subpectoral placement.

Methods: This was a retrospective review of patients who underwent immediate DTI breast reconstruction (prepectoral vs subpectoral) between 2011 and 2018. Demographics, clinical characteristics, complications, and patient-reported outcomes (BREAST-Q) were compared.

Results: Thirty-three patients (55 breasts) underwent prepectoral DTI, and 42 patients (69 breasts) underwent subpectoral DTI. Demographics were similar among groups. The number of breasts with preoperative ptosis lower than grade 2 was not significantly different between groups (29.1% vs 26.1%; P = 0.699). Median follow-up was 20.3 and 21 months in the prepectoral and subpectoral groups, respectively. Average mastectomy weight was 300 g (180-425 g) and 355 g (203-500 g). Average implant size was 410 cc (330-465 cc) and 425 cc (315-534 cc) in the prepectoral and subpectoral groups, respectively. Alloderm was used in all reconstructions. Total numbers of complications were 4 (7.2%) and 8 (11.6%) in the prepectoral and subpectoral groups, respectively (P = 0.227). BREAST-Q demonstrated mean patient satisfaction was high and similar among groups (75 and 73.9, P = 0.211).

Conclusions: Based on these results, we believe prepectoral DTI is safe, reliable, and a promising reconstructive option for selected patients, with equivalent results to other reconstructive options. Our present treatment recommendations are for patients who wish to maintain the same breast size and have minimal or no breast ptosis.
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http://dx.doi.org/10.1097/SAP.0000000000002028DOI Listing
April 2020

Potential role of iron in repair of inflammatory demyelinating lesions.

J Clin Invest 2019 10;129(10):4365-4376

Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.

Inflammatory destruction of iron-rich myelin is characteristic of multiple sclerosis (MS). Although iron is needed for oligodendrocytes to produce myelin during development, its deposition has also been linked to neurodegeneration and inflammation, including in MS. We report perivascular iron deposition in multiple sclerosis lesions that was mirrored in 72 lesions from 13 marmosets with experimental autoimmune encephalomyelitis. Iron accumulated mainly inside microglia/macrophages from 6 weeks after demyelination. Consistently, expression of transferrin receptor, the brain's main iron-influx protein, increased as lesions aged. Iron was uncorrelated with inflammation and postdated initial demyelination, suggesting that iron is not directly pathogenic. Iron homeostasis was at least partially restored in remyelinated, but not persistently demyelinated, lesions. Taken together, our results suggest that iron accumulation in the weeks after inflammatory demyelination may contribute to lesion repair rather than inflammatory demyelination per se.
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http://dx.doi.org/10.1172/JCI126809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763243PMC
October 2019

Two-Staged Implant-Based Breast Reconstruction: A Long-Term Outcome Study in a Young Population.

Medicina (Kaunas) 2019 Aug 14;55(8). Epub 2019 Aug 14.

Department of Surgery, Mayo Clinic, Rochester, MN 55904, USA.

Differences in patient anatomy and physiology exist between young and older patients undergoing breast reconstruction after mastectomy. Breast cancer has been described as being more aggressive, more likely to receive radiation, contralateral mastectomy, as well as bilateral reconstruction in young patients. Our purpose is to report long-term experience on two-staged implant-based breast reconstruction (IBR) in young females, with complication sub-analysis based on obesity and adjuvant radiation. Retrospective chart review of all consecutive young patients who underwent two-staged IBR at our institution, between 2000 and 2016, was performed. Patients between 15 and 40 years old with least 1-year follow-up were included. Univariate logistic regression models and receiver operating characteristic (ROC) curves were created. Overall 594 breasts met our inclusion criteria. The mean age was 34 years, and the median follow-up was 29.6 months. Final IBR was achieved in 98% of breasts. Overall, 12% of breasts had complications, leading to explantations of 5% of the devices. Adjuvant radiation was followed by higher rates of total device explantations ( = 0.003), while obese patients had higher rates of total complications ( < 0.001). For each point increase in BMI, the odds of developing complications increased 8.1% ( < 0.001); the cutoff BMI to predict higher complications was 24.81 kg/m. This population demonstrates high successful IBR completion and low explantation rates. These data suggest that obese women and those with planned adjuvant radiation deserve special counseling about their higher risk of complications.
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http://dx.doi.org/10.3390/medicina55080481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723805PMC
August 2019

Clinical trial of a humanized anti-IL-2/IL-15 receptor β chain in HAM/TSP.

Ann Clin Transl Neurol 2019 08 5;6(8):1383-1394. Epub 2019 Jul 5.

Viral Immunology Section, Division of Neuroimmunology and Neurovirology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, 20892.

Objective: Human T cell lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive, neurological disease. Chronic activation of CD8 T cells, as evidenced by increased spontaneous lymphoproliferation and HTLV-1-specific cytotoxic T cells, has been demonstrated in HAM/TSP patients. Since IL-2 and IL-15 stimulate memory CD8 T cell activity, these cytokines have been implicated in the immunopathogenesis of HAM/TSP. In this phase I trial, we evaluated the safety, pharmacokinetics, and ability of Hu-Mikβ1, a humanized monoclonal antibody directed toward the IL-2/IL-15 receptor β-chain (IL-2/IL-15Rβ: CD122), to saturate CD122 and regulate abnormal immune responses in patients with HAM/TSP by inhibition of IL-15 action.

Methods: Hu-Mikβ1 was administered intravenously at doses of 0.5 mg/kg, 1.0 mg/kg, or 1.5 mg/kg in a total of nine HAM/TSP patients. Five doses of Hu-Mikβ1 were administered at 3-week intervals. The clinical response was evaluated using standardized scales. Viral and immunologic outcome measures were examined including HTLV-1 proviral load, T cell phenotypic analysis and spontaneous lymphoproliferation in HAM/TSP patients.

Results: There was no significant toxicity associated with Hu-Mikβ1 administration in HAM/TSP patients. Saturation of CD122 by Hu-Mikβ1 was achieved in five out of nine HAM/TSP patients. Administration of Hu-Mikβ1 was associated with inhibition of aberrant CD8 T cell function including spontaneous lymphoproliferation and degranulation and IFN-γ expression, especially in HAM/TSP patients that achieved CD122 saturation.

Interpretation: The treatment with Hu-Mikβ1 had a number of immunological effects on HAM/TSP patients although no clinical efficacy was observed. We also did not see any dose-related toxicity.
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http://dx.doi.org/10.1002/acn3.50820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689682PMC
August 2019

Neuroimmunology of Human T-Lymphotropic Virus Type 1-Associated Myelopathy/Tropical Spastic Paraparesis.

Front Microbiol 2019 24;10:885. Epub 2019 Apr 24.

Viral Immunology Section, Division of Neuroimmunology and Neurovirology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States.

Human T-lymphotropic virus type 1 (HTLV-1) is the etiologic agent of both adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is clinically characterized by chronic progressive spastic paraparesis, urinary incontinence, and mild sensory disturbance. Given its well-characterized clinical presentation and pathophysiology, which is similar to the progressive forms of multiple sclerosis (MS), HAM/TSP is an ideal system to better understand other neuroimmunological disorders such as MS. Since the discovery of HAM/TSP, large numbers of clinical, virological, molecular, and immunological studies have been published. The host-virus interaction and host immune response play an important role for the development with HAM/TSP. HTLV-1-infected circulating T-cells invade the central nervous system (CNS) and cause an immunopathogenic response against virus and possibly components of the CNS. Neural damage and subsequent degeneration can cause severe disability in patients with HAM/TSP. Little progress has been made in the discovery of objective biomarkers for grading stages and predicting progression of disease and the development of molecular targeted therapy based on the underlying pathological mechanisms. We review the recent understanding of immunopathological mechanism of HAM/TSP and discuss the unmet need for research on this disease.
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http://dx.doi.org/10.3389/fmicb.2019.00885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492533PMC
April 2019

Extracellular Vesicles and Ebola Virus: A New Mechanism of Immune Evasion.

Viruses 2019 05 2;11(5). Epub 2019 May 2.

Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA 20110, USA.

Ebola virus (EBOV) disease can result in a range of symptoms anywhere from virtually asymptomatic to severe hemorrhagic fever during acute infection. Additionally, spans of asymptomatic persistence in recovering survivors is possible, during which transmission of the virus may occur. In acute infection, substantial cytokine storm and bystander lymphocyte apoptosis take place, resulting in uncontrolled, systemic inflammation in affected individuals. Recently, studies have demonstrated the presence of EBOV proteins VP40, glycoprotein (GP), and nucleoprotein (NP) packaged into extracellular vesicles (EVs) during infection. EVs containing EBOV proteins have been shown to induce apoptosis in recipient immune cells, as well as contain pro-inflammatory cytokines. In this manuscript, we review the current field of knowledge on EBOV EVs including the mechanisms of their biogenesis, their cargo and their effects in recipient cells. Furthermore, we discuss some of the effects that may be induced by EBOV EVs that have not yet been characterized and highlight the remaining questions and future directions.
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http://dx.doi.org/10.3390/v11050410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563240PMC
May 2019

Surgical Outcomes of Prepectoral Versus Subpectoral Implant-based Breast Reconstruction in Young Women.

Plast Reconstr Surg Glob Open 2019 Mar 13;7(3):e2119. Epub 2019 Mar 13.

Division of Plastic Surgery, Department of Surgery, Mayo Clinic, Rochester, Minn.

Background: Two-staged implant-based reconstruction (IBR) is the most common breast reconstructive modality. Recently, technological and surgical advances have encouraged surgeons to revisit prepectoral IBR. Data comparing prepectoral against subpectoral IBR in women under the age of 40 are lacking.

Methods: Retrospective chart review of patients under the age of 40 years old, who underwent immediate 2-staged IBR at our institution, was performed. Patient's demographics, clinical characteristics, operative details, and early surgical outcomes of prepectoral and subpectoral reconstruction were compared. Data with values of < 0.05 were considered statistically significant.

Results: Between 2012 and 2016, 100 patients (187 breasts) who underwent prepectoral and 69 patients (124 breasts) who underwent subpectoral IBR were included. Median follow-up was 17.9 and 17.5 months in the prepectoral and subpectoral groups, respectively. Total number of complications including both stages of reconstruction was 20 (10.7%) and 19 (15.3%) in the prepectoral and subpectoral groups, respectively ( = 0.227). Specific complications, including hematoma, seroma, skin flap necrosis, wound dehiscence, and breast infections, were not significantly different among groups. Ten (5.4%) devices, including implants and tissue expander, required explantation in the prepectoral group and 8 (6.5%) in the subpectoral group ( = 0.683). Explantation was most commonly due to infection (n = 14), and all of them occurred during the first stage ( < 0.001).

Conclusions: Early complications and implant explantation rates are comparable among prepectoral and subpectoral breast reconstruction in women under 40 years old. Based on these results, we believe that prepectoral IBR is a safe, reliable, and promising reconstructive option.
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http://dx.doi.org/10.1097/GOX.0000000000002119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467633PMC
March 2019

Infection with HHV-6 and its role in epilepsy.

Epilepsy Res 2019 07 29;153:34-39. Epub 2019 Mar 29.

Center for Neuroscience, Children's National Medical Center, George Washington University, 111 Michigan Ave NW, Washington, DC 20010, USA.

Infection with Human Herpesvirus-6 (HHV-6) has been associated with different epilepsy syndromes, including febrile seizures and status epilepticus, acute symptomatic seizures secondary to encephalitis and temporal lobe epilepsy. This neurotropic DNA virus is ubiquitous and primary infection occurs in up to 80% of children by age two years. While two viral variants have been identified, HHV-6B is the one that has been primarily linked to disease in humans, including epilepsy. After initial viremia, the virus can establish chronic latency in brain tissue, peripherally in tonsils and salivary glands and infect several different cell lines by binding to the complement regulator CD-46. In this review we will focus on discussing the evidence linking HHV-6 infection to different epilepsy syndromes and analyzing proposed pathogenic mechanisms.
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http://dx.doi.org/10.1016/j.eplepsyres.2019.03.016DOI Listing
July 2019

The "central vein sign" in inflammatory demyelination: The role of fibrillar collagen type I.

Ann Neurol 2019 06 30;85(6):934-942. Epub 2019 Mar 30.

Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, MD.

Accumulating evidence corroborates the role of the "central vein sign" in the radiological diagnosis of multiple sclerosis (MS). Here, we report human magnetic resonance imaging (MRI) and corresponding pathological data that inflammation-dependent intracerebral remodeling of the vessel wall is directly associated with the prominence of intralesional veins on susceptibility-based MRI. In adult marmosets with experimental autoimmune encephalomyelitis, vessel-wall fibrosis was detected early in the demyelinating process, even in lesions <2 weeks old, though fibrosis was more evident after 6 weeks. Vascular remodeling consisted of both luminal enlargement and eccentric thickening of the perivascular space (fibrillar collagen type I deposition) and affected almost exclusively white matter, but not subpial cortical, lesions. The long-term effect of vessel remodeling in MS lesions is currently unknown, but it might potentially affect tissue repair. ANN NEUROL 2019;85:934-942.
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http://dx.doi.org/10.1002/ana.25461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520117PMC
June 2019

Two-stage prepectoral breast reconstruction.

Gland Surg 2019 Feb;8(1):43-52

Jacobson Plastic Surgery, Rochester, MN, USA.

The options for prosthetic breast reconstruction have expanded and include prepectoral versus subpectoral location of devices as well as performing these operations in one- or two-stage. Current practice patterns are evolving toward the placement of devices in the prepectoral plane in a single stage. The authors' patient selection criteria and surgical technique were reviewed and organized in a step-by-step format. On and off label techniques for acellular dermal matrix (ADM) assembly were reviewed. A review of surgical outcomes was completed. Two-stage reconstruction confers several advantages such as reducing pressure on the mastectomy skin flaps, optimal implant selection for the second stage and the opportunity to revise the reconstruction, all of which can increase the likelihood of a successful outcome. This manuscript will review the indications, techniques, and outcomes following prepectoral, two-stage prosthetic breast reconstruction.
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http://dx.doi.org/10.21037/gs.2018.09.04DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378249PMC
February 2019
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