31 results on '"Whealy M"'
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2. Complementation analysis of pseudorabies virus gE and gI mutants in retinal ganglion cell neurotropism
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Enquist, L W, primary, Dubin, J, additional, Whealy, M E, additional, and Card, J P, additional
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- 1994
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3. Specific pseudorabies virus infection of the rat visual system requires both gI and gp63 glycoproteins
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Whealy, M E, primary, Card, J P, additional, Robbins, A K, additional, Dubin, J R, additional, Rziha, H J, additional, and Enquist, L W, additional
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- 1993
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4. A cellular function is required for pseudorabies virus envelope glycoprotein processing and virus egress
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Whealy, M E, primary, Robbins, A K, additional, Tufaro, F, additional, and Enquist, L W, additional
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- 1992
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5. Pseudorabies virus envelope glycoprotein gI influences both neurotropism and virulence during infection of the rat visual system
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Card, J P, primary, Whealy, M E, additional, Robbins, A K, additional, and Enquist, L W, additional
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- 1992
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6. The gIII glycoprotein of pseudorabies virus is involved in two distinct steps of virus attachment
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Zsak, L, primary, Sugg, N, additional, Ben-Porat, T, additional, Robbins, A K, additional, Whealy, M E, additional, and Enquist, L W, additional
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- 1991
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7. Effect of brefeldin A on alphaherpesvirus membrane protein glycosylation and virus egress
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Whealy, M E, primary, Card, J P, additional, Meade, R P, additional, Robbins, A K, additional, and Enquist, L W, additional
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- 1991
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8. The putative cytoplasmic domain of the pseudorabies virus envelope protein gIII, the herpes simplex virus type 1 glycoprotein C homolog, is not required for normal export and localization
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Solomon, K A, primary, Robbins, A K, additional, Whealy, M E, additional, and Enquist, L W, additional
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- 1990
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9. The export pathway of the pseudorabies virus gB homolog gII involves oligomer formation in the endoplasmic reticulum and protease processing in the Golgi apparatus
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Whealy, M E, primary, Robbins, A K, additional, and Enquist, L W, additional
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- 1990
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10. Site-specific insertion of DNA into a pseudorabies virus vector.
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Sauer, B, Whealy, M, Robbins, A, and Enquist, L
- Abstract
A simple, efficient method for introducing recombinant DNA into a herpesvirus vector and retrieving it at a later time has been developed. By using the Cre-lox site-specific recombination system of coliphage P1, DNA can be readily inserted in vitro into a pseudorabies virus (PRV) vector containing the lox recombination site. The vector PRV42 contains a lox site within the nonessential gIII gene, which encodes a virion envelope glycoprotein. Incubation in vitro of PRV42 DNA with Cre protein and a circular plasmid containing a lox site generates approximately 5% recombinant molecules having the plasmid integrated into the PRV genome at the lox site. Transfection of the reaction mixture into cultured cells allows recovery of the infectious recombinant virus, which is readily identified by a nondestructive "black-plaque assay" using a gIII-specific monoclonal antibody. PRV42 plaques stain black when treated with the gIII monoclonal antibody and a peroxidase-linked second anti-antibody because the lox site placed within the gIII gene of PRV42 does not destroy the gIII epitope. However, Cre-mediated integration of heterologous DNA at the lox site disrupts the gIII epitope so that the resulting recombinant virus produces white plaques. The recombinant virus is infectious, stable, and grows as well as the parental PRV42 vector. The inserted plasmid can be efficiently excised (greater than 50%) from viral DNA by Cre and recovered by transformation of Escherichia coli.
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- 1987
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11. The gene encoding the gIII envelope protein of pseudorabies virus vaccine strain Bartha contains a mutation affecting protein localization
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Robbins, A K, Ryan, J P, Whealy, M E, and Enquist, L W
- Abstract
Pseudorabies virus (PRV) vaccine strain Bartha has a diminished capacity to cause disease and harbors a variety of mutations affecting virulence. It has been reported that PRV Bartha produces virions with reduced amounts of the major envelope glycoprotein gIII. One hypothesis was that this phenotype was due to reduced expression of the gIII gene. In this report, we demonstrate that the reduced amount of gIII in virions was not mediated at the level of transcription, but rather reflected a defect in protein localization. We describe experiments with gene replacement technology to prove that the expression defect was closely linked to the gIII gene itself. Using pulse-chase experiments, we found a defect similar to that observed for certain signal sequence mutations of PRV Becker gIII. The Bartha gIII protein was translated, but was inefficiently introduced into the membrane protein export pathway. Consequently, only a fraction of the primary Bartha gIII translation product was glycosylated and matured. The remaining fraction stayed presumably in the cytoplasm, where it never became glycosylated or inserted into cell or virus membranes. The result was that Bartha-infected cells produced virions with reduced amounts of gIII in their envelopes. Comparison of the DNA sequence of the promoter and amino-terminal coding regions of Becker and Bartha gIII genes revealed a single base pair difference in Bartha, changing codon 14 of the signal sequence from a leucine (CTC) to a proline (CCC) codon. We suggest that the signal sequence mutation is responsible for the apparent reduced expression phenotype of this attenuated strain. This mutation represents, to our knowledge, the first reported natural signal sequence mutation in a herpesvirus glycoprotein.
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- 1989
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12. Analysis of pseudorabies virus glycoprotein gIII localization and modification by using novel infectious viral mutants carrying unique EcoRI sites
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Ryan, J P, Whealy, M E, Robbins, A K, and Enquist, L W
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We have constructed two pseudorabies virus (PRV) mutants, each with a unique EcoRI restriction site in the nonessential gIII envelope glycoprotein gene. Since no natural PRV isolate has been reported to contain EcoRI sites, the isolation and single-step growth curve analysis of these mutants established that PRV can carry such a site with little ill effect in tissue culture. Virus carrying these defined mutations produced novel gIII proteins that enabled us to begin functional assignment of protein localization information within the gIII gene. Specifically, one viral mutant contained an in-frame synthetic EcoRI linker sequence that was flanked on one side by the first one-third of the gIII gene and on the other side by the last one-third of the gene. The resulting protein lacked the middle one-third of the parental species, including five of eight putative N-linked glycosylation signals, but was still glycosylated and found in enveloped virions; it was not secreted into the medium. A second viral mutant contained an in-frame synthetic EcoRI linker sequence that additionally specified a nonsense codon at position 158, producing a gIII protein that was glycosylated and secreted into the medium; the fragment was not found in enveloped virions. By endoglycosidase and pulse-chase analyses, we established a precursor-product relationship between the various forms of gIII expressed in the parental and mutant strains, and perhaps determined certain features of the gIII protein that are required for its efficient export within the cell.
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- 1987
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13. The pseudorabies virus gII gene is closely related to the gB glycoprotein gene of herpes simplex virus
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Robbins, A K, Dorney, D J, Wathen, M W, Whealy, M E, Gold, C, Watson, R J, Holland, L E, Weed, S D, Levine, M, and Glorioso, J C
- Abstract
We have looked for conserved DNA sequences between four herpes simplex virus type 1 (HSV-1) glycoprotein genes encoding gB, gC, gD, and gE and pseudorabies virus (PRV) DNA, HSV-1 DNA fragments representing these four glycoprotein-coding sequences were hybridized to restriction enzyme fragments of PRV DNA by the Southern blot procedure. Specific hybridization was observed only when HSV-1 gB DNA was used as probe. This region of hybridization was localized to a 5.2-kilobase (kb) region mapping at approximately 0.15 map units on the PRV genome. Northern blot (RNA blot) analysis, with a 1.2-kb probe derived from this segment, revealed a predominant hybridizing RNA species of approximately 3 kb in PRV-infected PK15 cells. DNA sequence analysis of the region corresponding to this RNA revealed a single large open reading frame with significant nucleotide homology with the gB gene of HSV-1 KOS 321. In addition, the beginning of the sequenced PRV region also contained the end of an open reading frame with amino acid homology to HSV-1 ICP 18.5, a protein that may be involved in viral glycoprotein transport. This sequence partially overlaps the PRV gB homolog coding sequence. We have shown that the PRV gene with homology to HSV-1 gB encoded the gII glycoprotein gene by expressing a 765-base-pair segment of the PRV open reading frame in Escherichia coli as a protein fused to beta-galactosidase. Antiserum, raised in rabbits, against this fusion protein immunoprecipitated a specific family of PRV glycoproteins of apparent molecular mass 110, 68, and 55 kilodaltons that have been identified as the gII family of glycoproteins. Analysis of the predicted amino acid sequence indicated that the PRV gII protein shares 50% amino acid homology with the aligned HSV-1 gB protein. All 10 cysteine residues located outside of the signal sequence, as well as 4 of 6 potential N-linked glycosylation sites, were conserved between the two proteins. The primary protein sequence for HSV-1 gB regions known to be involved in the rate of virus entry into the cells and cell-cell fusion, as well as regions known to be associated with monoclonal antibody resistance, were highly homologous with the PRV protein sequence. Furthermore, monospecific antibody made against PRV gII immunoprecipitated HSV-1 gB from infected cells. Taken together, these findings suggest significant conservation of structure and function between the two proteins and may indicate a common evolutionary history.
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- 1987
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14. Characterization of a pseudorabies virus glycoprotein gene with homology to herpes simplex virus type 1 and type 2 glycoprotein C
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Robbins, A K, Watson, R J, Whealy, M E, Hays, W W, and Enquist, L W
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A pseudorabies virus (Becker strain) glycoprotein gene was located in the UL region at map position 0.40. The gene was identified by using open reading frame Escherichia coli plasmid expression vectors and specific antibody reagents. A 1.55-kilobase unspliced transcript from the gene was detected in pseudorabies virus-infected tissue culture cells. The DNA sequence revealed a single open reading frame of 1,437 base pairs encoding 479 amino acids. The predicted primary translation product has a molecular weight of 50,860 and contains features of a typical herpesvirus glycoprotein. An E. coli expression plasmid was constructed that contained essentially all of the open reading frame for this gene. Antibodies raised in rabbits against the protein expressed in bacteria by this plasmid immunoprecipitated pseudorabies virus-specific glycoproteins of 92,000 and 74,000 daltons from infected cell extracts. It is likely that these two forms represent different glycosylation states of the protein.
- Published
- 1986
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15. Replacement of the pseudorabies virus glycoprotein gIII gene with its postulated homolog, the glycoprotein gC gene of herpes simplex virus type 1
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Whealy, M E, Robbins, A K, and Enquist, L W
- Abstract
gIII, the major envelope glycoprotein of pseudorabies virus (PRV), shares approximately 20% amino acid similarity with glycoprotein gC of herpes simplex virus type 1 (HSV-1) and HSV-2. We describe here our first experiments on the potential conservation of function between these two genes and gene products. We constructed PRV recombinants in which the gIII gene and regulatory sequences have been replaced with the entire HSV-1 gC gene and its regulatory sequences. The gC promoter functions in the PRV genome, and authentic HSV-1 gC protein is produced, albeit at a low level, in infected cells. The gC protein is present at the cell surface but cannot be detected in the PRV envelope.
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- 1989
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16. A herpesvirus vector for expression of glycosylated membrane antigens: fusion proteins of pseudorabies virus gIII and human immunodeficiency virus type 1 envelope glycoproteins
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Whealy, M E, Baumeister, K, Robbins, A K, and Enquist, L W
- Abstract
We describe experiments using the swine herpesvirus, pseudorabies virus (PRV), as a vector for expression of hybrid membrane protein genes. In particular, we present the construction and analysis of three infectious PRV mutants expressing chimeric viral membrane proteins composed of portions of the PRV envelope glycoprotein gIII and of the human retrovirus, human immunodeficiency virus type 1 (HIV-1), envelope glycoproteins gp120 and gp41. All of the chimeric genes contain the transcription control sequences and the first 157 codons of PRV gIII (known to contain signals sufficient for efficient export of the encoded peptide out of the cell) fused to different regions of the HIV-1 envelope. The mutant viruses express novel glycosylated fusion proteins that are immunoprecipitated by polyvalent sera specific for gIII, as well as acquired immunodeficiency syndrome patient sera. The levels of expression are lower than expected due primarily to instability or altered processing of the hybrid mRNA. We could not detect cleavage of chimeric proteins carrying the gp120-gp41 protease processing site. The use of localization signals contained within herpesvirus membrane proteins to direct chimeric proteins to desired cellular locations is discussed.
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- 1988
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17. An amino-terminal deletion mutation of pseudorabies virus glycoprotein gIII affects protein localization and RNA accumulation
- Author
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Enquist, L W, Keeler, C L, Robbins, A K, Ryan, J P, and Whealy, M E
- Abstract
We have constructed a pseudorabies virus mutant that contains virtually a complete deletion of the predicted signal sequence coding region for a nonessential envelope glycoprotein, gIII. No signal sequence mutants have been reported previously for a herpesvirus glycoprotein. Through endoglycosidase treatments and pulse-chase analysis, we have determined that the mutant gIII protein is not posttranslationally modified like the wild-type polypeptide, but rather is present as a single, stable species within the infected cell. The mutant polypeptide cannot be detected in the virus envelope, nor is it aberrantly localized to the tissue culture medium. Immunofluorescence studies have indicated that the mutant protein also is not localized to the surfaces of infected cells. In addition, Northern (RNA) and slot blot analyses, as well as in vitro translation experiments using infected-cell cytoplasmic RNA, have indicated that the mutant gIII allele is expressed at lower levels than the wild-type gene is. This is despite the fact that no alterations have been made upstream of the gIII coding sequence. From these results, it appears that the first 22 amino acids of the wild-type gIII protein define a necessary signal peptide that is responsible for at least the correct initiation of translocation and subsequent glycosylation of the gIII envelope glycoprotein within infected cells.
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- 1988
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18. Pseudorabies virus glycoprotein gIII is required for efficient virus growth in tissue culture
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Whealy, M E, Robbins, A K, and Enquist, L W
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Glycoprotein gIII of pseudorabies virus is a major antigen found in the envelopes of virus particles as well as in and on the surfaces of infected cells. It is not an essential gene product for virus growth in tissue culture. In this report, we provide evidence that, although it is not essential, the gIII protein is required for efficient virus growth and that gIII mutants are quickly outgrown by wild-type virus in mixed infections.
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- 1988
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19. Pseudorabies virus gene encoding glycoprotein gIII is not essential for growth in tissue culture
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Robbins, A K, Whealy, M E, Watson, R J, and Enquist, L W
- Abstract
We have established that in the Becker strain of pseudorabies virus (PRV), the glycoprotein gIII gene is not essential for growth in cell culture. This was accomplished by construction and analysis of viral mutants containing two defined deletion mutations affecting the gIII gene. These mutations were first constructed in vitro and introduced into Escherichia coli expression plasmids to verify structure and protein production. Each mutation was then crossed onto PRV by cotransfection of plasmid DNA and parental viral DNA by using gIII-specific monoclonal antibodies as selective and screening reagents. One resultant virus strain, PRV-2, contained an in-frame deletion of a 402-base-pair (bp) SacI fragment contained within the gIII gene. Another virus strain, PRV-10, contained a deletion of a 1,480-bp XhoI fragment removing 230 bp of the upstream, putative transcriptional control sequences and 87% of the gIII coding sequence. The deletion mutants were compared with parental virus by analysis of virion DNA, gIII specific RNA, and proteins reacting with gIII specific antibodies. Upon infection of PK15 cells, the deletion mutants did not produce any proteins that reacted with two gIII specific monoclonal antibodies. However, two species of truncated glycosylated proteins were observed in PRV-2 infected cells that reacted with antiserum raised against bacterially produced gIII protein. PRV-10 produced no detectable gIII-specific RNA or protein. PRV-10 could be propagated without difficulty in tissue culture. Virus particles lacking gIII were indistinguishable from parental PRV virus particles by analysis of infected-cell thin sections in the electron microscope. We therefore conclude that expression of the gIII gene was not absolutely essential for PRV growth in tissue culture.
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- 1986
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20. NAPC to start Greece's first oil production
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Whealy,m Richard
- Subjects
Greece -- Natural resources ,North Aegean Petroleum Co. -- Management ,Petroleum industry -- Greece ,Oil well drilling, Submarine -- Greece ,Business ,Petroleum, energy and mining industries - Abstract
North Aegean Petroleum begins oil production in Aegean Sea; production begins in Prinos oil field and Kavala gas field.
- Published
- 1981
21. Advancing toward precision migraine treatment: Predicting responses to preventive medications with machine learning models based on patient and migraine features.
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Chiang CC, Schwedt TJ, Dumkrieger G, Wang L, Chao CJ, Ouellette HA, Banerjee I, Chen YC, Jones BM, Burke KM, Wang H, Murray AM, Montenegro MM, Stern JI, Whealy M, Kissoon N, and Cutrer FM
- Subjects
- Humans, Female, Male, Adult, Middle Aged, Antidepressive Agents, Tricyclic therapeutic use, Cohort Studies, Precision Medicine, Adrenergic beta-Antagonists therapeutic use, Topiramate administration & dosage, Topiramate pharmacology, Treatment Outcome, Migraine Disorders drug therapy, Migraine Disorders prevention & control, Machine Learning
- Abstract
Objective: To develop machine learning models using patient and migraine features that can predict treatment responses to commonly used migraine preventive medications., Background: Currently, there is no accurate way to predict response to migraine preventive medications, and the standard trial-and-error approach is inefficient., Methods: In this cohort study, we analyzed data from the Mayo Clinic Headache database prospectively collected from 2001 to December 2023. Adult patients with migraine completed questionnaires during their initial headache consultation to record detailed clinical features and then at each follow-up to track preventive medication changes and monthly headache days. We included patients treated with at least one of the following migraine preventive medications: topiramate, beta-blockers (propranolol, metoprolol, atenolol, nadolol, timolol), tricyclic antidepressants (amitriptyline, nortriptyline), verapamil, gabapentin, onabotulinumtoxinA, and calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) (erenumab, fremanezumab, galcanezumab, eptinezumab). We pre-trained a deep neural network, "TabNet," using 145 variables, then employed TabNet-embedded data to construct prediction models for each medication to predict binary outcomes (responder vs. non-responder). A treatment responder was defined as having at least a 30% reduction in monthly headache days from baseline. All model performances were evaluated, and metrics were reported in the held-out test set (train 85%, test 15%). SHapley Additive exPlanations (SHAP) were conducted to determine variable importance., Results: Our final analysis included 4260 patients. The responder rate for each medication ranged from 28.7% to 34.9%, and the mean time to treatment outcome for each medication ranged from 151.3 to 209.5 days. The CGRP mAb prediction model achieved a high area under the receiver operating characteristics curve (AUC) of 0.825 (95% confidence interval [CI] 0.726, 0.920) and an accuracy of 0.80 (95% CI 0.70, 0.88). The AUCs of prediction models for beta-blockers, tricyclic antidepressants, topiramate, verapamil, gabapentin, and onabotulinumtoxinA were: 0.664 (95% CI 0.579, 0.745), 0.611 (95% CI 0.562, 0.682), 0.605 (95% CI 0.520, 0.688), 0.673 (95% CI 0.569, 0.724), 0.628 (0.533, 0.661), and 0.581 (95% CI 0.550, 0.632), respectively. Baseline monthly headache days, age, body mass index (BMI), duration of migraine attacks, responses to previous medication trials, cranial autonomic symptoms, family history of headache, and migraine attack triggers were among the most important variables across all models. A variable could have different contributions; for example, lower BMI predicts responsiveness to CGRP mAbs and beta-blockers, while higher BMI predicts responsiveness to onabotulinumtoxinA, topiramate, and gabapentin., Conclusion: We developed an accurate prediction model for CGRP mAbs treatment response, leveraging detailed migraine features gathered from a headache questionnaire before starting treatment. Employing the same methods, the model performances for other medications were less impressive, though similar to the machine learning models reported in the literature for other diseases. This may be due to CGRP mAbs being migraine-specific. Incorporating medical comorbidities, genomic, and imaging factors might enhance the model performance. We demonstrated that migraine characteristics are important in predicting treatment responses and identified the most crucial predictors for each of the seven types of preventive medications. Our results suggest that precision migraine treatment is feasible., (© 2024 American Headache Society.)
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- 2024
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22. Clinical and imaging outcomes of 100 patients with cerebrospinal fluid-venous fistulas treated by transvenous embolization.
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Brinjikji W, Madhavan A, Garza I, Whealy M, Kissoon N, Mark I, Morris PP, Verdoorn J, Benson JC, Atkinson JLD, Kobeissi H, and Cutsforth-Gregory JK
- Abstract
Background: Cerebrospinal fluid-venous fistulas (CSFVF) are a common cause of spontaneous intracranial hypotension (SIH). Transvenous embolization has emerged as a reliable treatment option. We review the clinical presentation, imaging, and clinical outcomes of 100 consecutive CSFVF patients who underwent embolization over 2 years., Methods: Baseline clinical characteristics, imaging findings (including Bern SIH score), technical outcomes, and long-term imaging and clinical outcomes were collected. All patients had at least 3 months of clinical follow-up and had baseline MRI. 99/100 patients underwent follow-up imaging at ≥3 months post-treatment., Results: 100 patients were included. Mean imaging and clinical follow-up duration was 8.3±7.7 months and 15.0±6.8 months, respectively. The mean duration of symptoms before embolization was 40.9±52 months. Mean baseline Bern SIH score was 5.9±3.3. The most common baseline symptoms were headache (96 patients), tinnitus (55 patients), and cognitive dysfunction (44 patients). Technical success rate was 100%. Mean post-treatment Bern SIH score was 0.9±1.6 (P<0.0001). Following treatment, 95% of patients reported significant improvement or resolution in symptoms (58 patients reporting resolution and 37 reporting improvement). 5 patients reported no improvement. There were no major procedural or periprocedural complications. 10 patients had minor procedural complications that did not result in any change in management (Onyx emboli, venous perforation). 19 patients had rebound intracranial hypertension requiring acetazolamide therapy. 7 patients had recurrent fistula at the initially treated level., Conclusions: Transvenous embolization of CSFVF in SIH patients is safe and effective with a 95% treatment response, significant improvement in imaging outcomes, and a very low rate of complications., Competing Interests: Competing interests: WB holds equity in Nested Knowledge, Superior Medical Editors, Piraeus Medical, Sonoris Medical, and MIVI Neurovascular. He receives royalties from Medtronic and Balloon Guide Catheter Technology. He receives consulting fees from Medtronic, Stryker, Imperative Care, Microvention, MIVI Neurovascular, Cerenovus, Asahi, and Balt. He serves in a leadership or fiduciary role for MIVI Neurovascular, Marblehead Medical LLC, Interventional Neuroradiology (Editor in Chief), Piraeus Medical, and WFITN. The remaining authors declare no conflicts of interest., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2024
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23. The 5-HT 1B and 5-HT 1D agonists in acute migraine therapy: Ergotamine, dihydroergotamine, and the triptans.
- Author
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Whealy M and Becker WJ
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- Humans, Dihydroergotamine therapeutic use, Serotonin therapeutic use, Tryptamines therapeutic use, Ergotamine therapeutic use, Migraine Disorders drug therapy, Serotonin 5-HT1 Receptor Agonists therapeutic use
- Abstract
The advent of the triptans revolutionized acute migraine treatment. The older migraine-specific drugs, the ergot alkaloids (ergotamine and dihydroergotamine), also relieve migraine attacks through agonism at the 5-HT
1B and 5-HT1D receptors, but the triptans have much greater specificity for these receptors. Unlike the ergot alkaloids, the triptans do not activate many other receptor types, and therefore are much better tolerated. This reduction in side effects greatly enhanced their clinical utility as it allowed a far greater proportion of patients to take a full therapeutic dose. As a result, the clinical use of ergotamine is minimal today, although dihydroergotamine still has a significant clinical role. There is extensive evidence that the seven triptans available today, sumatriptan, zolmitriptan, rizatriptan, eletriptan, naratriptan, almotriptan, and frovatriptan, are effective in the acute treatment of migraine. Available formulations include oral tablets, orally dissolving tablets, subcutaneous injections, nasal sprays, and in some countries, rectal suppositories. For optimal benefit, therapy needs to be individualized for a given patient both regarding the triptan chosen and the formulation. This chapter discusses the ergot alkaloids and the triptans, including mechanism of action, evidence for efficacy, clinical use, and adverse effects., (Copyright © 2024 Elsevier B.V. All rights reserved, including those for text and data mining, AI training, and similar technologies.)- Published
- 2024
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24. Clinical and imaging outcomes of cerebrospinal fluid-venous fistula embolization.
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Brinjikji W, Garza I, Whealy M, Kissoon N, Atkinson JLD, Savastano L, Madhavan A, and Cutsforth-Gregory J
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- Aged, Female, Headache diagnostic imaging, Headache etiology, Headache therapy, Humans, Male, Middle Aged, Myelography adverse effects, Myelography methods, Polyvinyls, Retrospective Studies, Embolization, Therapeutic adverse effects, Embolization, Therapeutic methods, Fistula complications, Intracranial Hypotension diagnostic imaging, Intracranial Hypotension etiology, Intracranial Hypotension therapy
- Abstract
Background: We report outcomes of spontaneous intracranial hypotension (SIH) patients who underwent transvenous embolization of cerebrospinal fluid-venous fistulas (CSFVFs) confirmed on digital subtraction myelography (DSM) performed at our institution., Methods: This is a retrospective evaluation of a prospectively collected database of SIH patients who underwent transvenous embolization of CSFVFs. Only patients who had fistulas confirmed on DSM performed at our institution were included. All patients had a baseline MRI and an MRI performed at least 90 days post-embolization, as well as clinical evaluation using the six item Headache Impact Test (HIT-6) and the Patient Global Impression of Change (PGIC) scales. Paired t-test was used to report changes in Bern MRI scores and HIT-6 scores at follow-up., Results: 40 patients were included (29 female, 11 male). Mean age was 57.4±10.3 years. Mean Bern score improved from 5.7±3.0 at baseline to 1.3±2.0 at follow-up (p<0.0001). Mean HIT-6 score at baseline was 67.2±11.1 and at follow-up was 41.5±10.1 (p<0.0001). Median PGIC was 1, with 36 patients (90.0%) reporting at least minimal improvement and 32 patients (82.5%) reporting much or very much improvement. Complications included persistent local site pain in 12 patients (30%), suspected rebound intracranial hypertension requiring medical intervention in 7 patients (17.5%), and asymptomatic tiny Onyx emboli to the lungs in 3 patients (7.5%)., Conclusions: Transvenous embolization of CSFVFs using Onyx is safe and effective, resulting in significant improvement in headache and overall clinical outcomes in nearly 90% of patients, and substantial improvements in brain MRI abnormalities., Competing Interests: Competing interests: WB consultant for Medtronic, Microvention, Stryker, Cerenovus, MIVI. No other financial relationships., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2022
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25. Fibromyalgia in migraine: a retrospective cohort study.
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Whealy M, Nanda S, Vincent A, Mandrekar J, and Cutrer FM
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- Adult, Aged, Comorbidity, Databases, Factual, Disabled Persons, Female, Humans, Male, Middle Aged, Retrospective Studies, Fibromyalgia epidemiology, Migraine Disorders epidemiology
- Abstract
Background: Migraine is a common and disabling disorder. Fibromyalgia has been shown to be commonly comorbid in patients with migraine and can intensify disability. The aim of this study was to determine if patients with co-morbid fibromyalgia and migraine report more depressive symptoms, have more headache related disability, or report higher intensity of headache as compared to patients with migraine only. Cases of comorbid fibromyalgia and migraine were identified using a prospectively maintained headache database at Mayo Clinic Rochester. One-hundred and fifty seven cases and 471 controls were identified using this database and the Mayo Clinic electronic medical record., Findings: Depressive symptoms as assessed by PHQ-9, intensity of headache, and migraine related disability as assessed by MIDAS were primary measures used to compare migraine patients with comorbid fibromyalgia versus those without. Patients with comorbid fibromyalgia reported significantly higher PHQ-9 scores (OR 1.08, p < .0001) and headache intensity scores (OR 1.149, p = .007). There was no significant difference in migraine related disability (OR 1.002, p = .075). Patients with fibromyalgia were more likely to score in a higher category of depression severity (OR 1.467, p < .0001) and more likely to score in a higher category of migraine related disability (OR 1.23, p = .004)., Conclusion: Patients with comorbid fibromyalgia and migraine report more depressive symptoms, higher headache intensity, and are more likely to have severe headache related disability as compared to controls without fibromyalgia. Clinicians who care for patients with migraine may consider screening for comorbid fibromyalgia particularly in patients with moderate to severe depressive symptoms, high headache intensity and/or high headache related disability. This is the first matched study to look at these characterisitcs, and it replicates previous findings from unmatched studies.
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- 2018
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26. Prevalence and Risk Factors of Peri-ictal Autonomic Changes in Children With Temporal Lobe Seizures.
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Whealy M, Wirrell E, Wong-Kisiel L, Nickels K, and Payne ET
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- Adolescent, Brugada Syndrome, Child, Child, Preschool, Female, Humans, Male, Prevalence, Prospective Studies, Retrospective Studies, Risk Factors, Seizures epidemiology, Seizures physiopathology, Autonomic Nervous System Diseases epidemiology, Autonomic Nervous System Diseases physiopathology, Epilepsy, Temporal Lobe epidemiology, Epilepsy, Temporal Lobe physiopathology
- Abstract
Background: We determined the prevalence of signs and symptoms of autonomic dysfunction in seizures of temporal lobe onset in children., Methods: We evaluated the prevalence and risk factors of peri-ictal autonomic changes in temporal lobe onset seizures in children from a single-center pediatric epilepsy monitoring unit between June 1, 2009 and October 31, 2013. Age, gender, epilepsy etiology, current antiepileptic drug therapy, ictal electroencephalographic lateralization, brain magnetic resonance imaging results, and the presence of generalized tonic-clonic seizures over the preceding year were recorded from medical record review., Results: Forty-nine children were identified (55% male, median age 10.1 years [interquartile range 5.5 to 13.9 years]). Overall, peri-ictal autonomic changes were observed in 32 of 49 patients (66%) and 91 of 172 evaluated seizures (53%). Tachycardia (51%), oxygen desaturation (33%), and salivation (27%) were the most frequent autonomic changes identified. Bradycardia occurred in one patient (2%)., Conclusions: Among pediatric patients with temporal lobe seizures, peri-ictal autonomic changes are frequent yet seldom require intervention., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2017
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27. Influence of infectious dose upon productive replication and transynaptic passage of pseudorabies virus in rat central nervous system.
- Author
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Card JP, Dubin JR, Whealy ME, and Enquist LW
- Subjects
- Animals, Biological Transport physiology, Brain cytology, Brain metabolism, Cells, Cultured, Eye, Fibroblasts cytology, Fibroblasts virology, Herpesvirus 1, Suid metabolism, Kidney cytology, Male, Microinjections, Neurons metabolism, Neurons ultrastructure, Neurons virology, Optic Nerve cytology, Optic Nerve virology, Rats, Rats, Sprague-Dawley, Swine, Synapses metabolism, Brain virology, Herpesvirus 1, Suid growth & development, Pseudorabies metabolism, Synapses virology, Virus Replication
- Abstract
Pseudorabies virus (PRV) is a neurotropic swine alpha herpesvirus that characteristically invades the nervous system and replicates within synaptically-linked populations of neurons. The invasive characteristics and ability of this family of viruses to replicate in neurons of the central nervous system (CNS) have been exploited to map functionally related populations of neurons in a variety of systems. In this report, we examined the effects of strain and concentration on the ability of PRV to infect retinal ganglion cells and pass transneuronally through central visual circuits. We find that the ability of virulent (PRV-Becker) and attenuated (PRV-Bartha) strains of PRV to produce a productive infection of visual circuitry is directly dependent upon the infectious of the injected virus. Injections of at least 10(5) total plaque forming units produce 100% infectivity, whereas lower infectious doses substantially reduce the percentage of animals exhibiting productive infection via this route of inoculation. Furthermore, the virulent strain of PRV consistently infects a higher percentage of animals across a broader range of titers than attenuated virus. These data demonstrate that viral titer and strain are important variables that should be considered in the design of studies and interpretation of data derived from investigations employing this pathogen for circuit analysis.
- Published
- 1995
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28. Overall signal sequence hydrophobicity determines the in vivo translocation efficiency of a herpesvirus glycoprotein.
- Author
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Ryan P, Robbins A, Whealy M, and Enquist LW
- Subjects
- Amino Acid Sequence, Animals, Base Sequence, Biological Transport, Active, Cell Line, Cell Membrane metabolism, DNA Mutational Analysis, DNA, Viral genetics, Herpesvirus 1, Suid metabolism, Molecular Sequence Data, Mutagenesis, Site-Directed, Protein Sorting Signals genetics, Swine, Viral Envelope Proteins metabolism, Herpesvirus 1, Suid genetics, Viral Envelope Proteins genetics
- Abstract
We have described three mutant strains of Pseudorabies virus that contain mutations in the signal sequence coding region of a nonessential envelope glycoprotein, gIII. The alterations disrupt, truncate, or eliminate the hydrophobic core domain of the signal sequence. Each mutant was assayed for its ability to promote the translocation of gIII across the endoplasmic reticulum membrane and the subsequent localization of the mature form of the glycoprotein to the infected cell surface or the virus envelope. Our results confirm and extend findings in other systems that the overall hydrophobicity of the signal sequence core region is a major determinant of translocation efficiency. We were unable to correlate simply the length of the core or the average hydrophobicity of core residues with export efficiency. Because our work involved the use of infectious virus mutants, we were able to identify a virus defect associated with a complete block in gIII export. This defect will facilitate a pseudo-reversion analysis of gIII signal sequence function.
- Published
- 1993
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29. Two alpha-herpesvirus strains are transported differentially in the rodent visual system.
- Author
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Card JP, Whealy ME, Robbins AK, Moore RY, and Enquist LW
- Subjects
- Animals, Axonal Transport, Cell Line, Herpesvirus 1, Suid pathogenicity, Male, Rats, Rats, Inbred Strains, Species Specificity, Swine, Time Factors, Virulence, Brain microbiology, Herpesvirus 1, Suid physiology, Neurons microbiology, Pseudorabies physiopathology, Retina microbiology, Visual Pathways microbiology
- Abstract
Uptake and transneuronal passage of wild-type and attenuated strains of a swine alpha-herpesvirus (pseudorabies [PRV]) were examined in rat visual projections. Both strains of virus infected subpopulations of retinal ganglion cells and passed transneuronally to infect retino-recipient neurons in the forebrain. However, the location of infected forebrain neurons varied with the strain of virus. Intravitreal injection of wild-type virus produced two temporally separated waves of infection that eventually reached all known retino-recipient regions of the central neuraxis. By contrast, the attenuated strain of PRV selectively infected a functionally distinct subset of retinal ganglion cells with restricted central projections. The data indicate that projection-specific groups of ganglion cells are differentially susceptible to the two strains of virus and suggest that this sensitivity may be receptor mediated.
- Published
- 1991
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30. Neurotropic properties of pseudorabies virus: uptake and transneuronal passage in the rat central nervous system.
- Author
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Card JP, Rinaman L, Schwaber JS, Miselis RR, Whealy ME, Robbins AK, and Enquist LW
- Subjects
- Animals, Brain Stem microbiology, Esophagus microbiology, Injections, Male, Neural Pathways microbiology, Neurons microbiology, Rats, Rats, Inbred Strains, Stomach microbiology, Time Factors, Tongue microbiology, Virus Replication, Central Nervous System microbiology, Herpesvirus 1, Suid physiology, Neurons physiology
- Abstract
Uptake, replication, and transneuronal passage of a swine neurotropic herpesvirus (pseudorabies virus, PRV) was evaluated in the rat CNS. PRV was localized in neural circuits innervating the tongue, stomach, esophagus and eye with light microscopic immunohistochemistry. In each instance, the distribution of PRV-immunoreactive neurons was entirely consistent with that observed following injection of cholera toxin-horseradish peroxidase conjugate (CT-HRP). Injections of the tongue resulted in retrograde transport of PRV and CT-HRP to hypoglossal motor neurons, while preganglionic neurons in the dorsal motor vagal nucleus or somatic motor neurons in the nucleus ambiguus were labeled following injections of the stomach or esophagus, respectively. At longer times after infection, viral antigens were found in astrocytes adjacent to infected neurons and their efferent axons and second-order neuron labeling became apparent. The distribution of second-order neurons was also entirely dependent upon the site of PRV injection. Following tongue injection, second-order neurons were observed in the trigeminal complex, the brain-stem tegmentum and in monoaminergic cell groups. Injection of the stomach or esophagus led to second-order neuron labeling confined to distinct subdivisions of the neucleus of the solitary tract and monoaminergic cell groups. Comparative quantitative analysis of the number of PRV immunoreactive neurons present in the diencephalon and brain stem following injection of virus into both the eye and stomach musculature of the same animal demonstrated that retrograde transport of PRV from the viscera was more efficient and occurred at a much faster rate than anterograde transport of virus. These data demonstrate projection-specific transport of PRV in the nervous system and provide further insight into the means through which this neurotropic virus infects the nervous system.
- Published
- 1990
31. Construction of an infectious pseudorabies virus recombinant expressing a glycoprotein gIII-beta-galactosidase fusion protein.
- Author
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Keeler CL Jr, Whealy ME, and Enquist LW
- Subjects
- Antigens, Viral genetics, Chromosome Mapping, Escherichia coli genetics, Gene Expression Regulation, Glycosylation, Herpesvirus 1, Suid growth & development, Herpesvirus 1, Suid immunology, Hexosaminidases, Immunologic Techniques, Mutation, Protein Processing, Post-Translational, Viral Envelope Proteins immunology, beta-Galactosidase genetics, Herpesvirus 1, Suid genetics, Recombinant Fusion Proteins genetics, Recombinant Proteins genetics, Viral Envelope Proteins genetics
- Abstract
An infectious herpesvirus mutant has been constructed in which a major structural envelope glycoprotein gene was replaced by a hybrid gene encoding a novel fusion protein consisting of the N-terminus of the viral glycoprotein joined to Escherichia coli beta-galactosidase (beta Gal). Specifically, we fused DNA encoding the first 157 amino acids of the structural glycoprotein gIII from pseudorabies virus strain Becker to the E. coli lacZ gene in a bacterial expression vector. The resulting hybrid gene was then used to replace the wild-type gIII gene in the virus by cotransfection of plasmid and viral DNA. The desired viral recombinants were identified by their inability to react with specific monoclonal antibodies that recognized only wild-type gIII protein. One such mutant virus, PRV-Z1, was chosen for further analysis. PRV-Z1 expressed a glycosylated gIII-beta Gal fusion protein after infection of PK15 cells. The fusion protein has no demonstrable beta Gal activity and, although glycosylated, remains sensitive to the enzyme endo-beta-N-acetylglucosaminidase H, unlike the mature gIII gene product, indicating that the fusion protein was incompletely processed.
- Published
- 1986
- Full Text
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