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ABSTRACT: OBJECTIVE: The objective of this randomized, double-blind, placebo-controlled, crossover study was to examine if patients with optic neuropathy would derive a therapeutic benefit from 4-aminopyridine (4-AP) treatment. Furthermore, the study was intended to determine if patients with certain P100 latencies or retinal nerve fiber layer (RNFL) measures would be more likely to respond to therapy. METHODS: Patients were enrolled in a randomized, placebo-controlled, double-blind, crossover study of 10 weeks duration. Patients underwent visual evoked potentials (VEP), optical coherence tomography (OCT), and visual acuity before starting 5 weeks of either placebo or 4-AP. After 5 weeks, they completed a second evaluation (VEP, OCT, and visual acuity) and were crossed over between treatment arms. Five weeks later, they had their final evaluation. All investigators were blinded to treatment arm until after data analysis. RESULTS: On average, patients had faster P100s on 4-AP when compared to placebo. A subset of patients had distinct responses to 4-AP as measured by improvements in visual acuity. Finally, eyes with an RNFL measure between 60 and 80 µm had the highest response rate. CONCLUSIONS: 4-Aminopyridine is useful for improving vision in patients with demyelinating optic neuropathy. Future clinical trials may be able to enrich a patient population for potential responders using OCT and VEP measures. Selecting patients for future trials should use RNFL measures as part of inclusion/exclusion criteria. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence supporting the use of 4-AP in certain patients with optic neuropathy to improve visual function (patients with RNFL between 60 and 80 µm).
Neurology 04/2013; · 8.31 Impact Factor
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Benjamin M Greenberg,
Laura Balcer,
Peter A Calabresi,
Bruce Cree,
Anne Cross,
Teresa Frohman,
Ralf Gold,
Eva Havrdova,
Bernhard Hemmer,
Bernd C Kieseier,
Robert Lisak,
Aaron Miller,
Michael K Racke,
Lawrence Steinman,
Olaf Stuve,
Heinz Wiendl, Elliot Frohman
JAMA neurology. 02/2013; 70(2):248-51.
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ABSTRACT: BACKGROUND: Transverse myelitis (TM) is an inflammatory disease of the spinal cord. In pediatric TM patients, cognitive and psychological problems have been described only anecdotally. OBJECTIVES: Study aims include describing cognitive dysfunction among a cohort of pediatric TM patients as well as qualitatively exploring the impact of depression, medication, and fatigue on cognitive functioning. METHODS: Twenty-four consecutive TM patients referred to a pediatric demyelinating diseases clinic completed neuropsychological screening. Means, standard deviations (SD), and percentages of patients performing at or below 1.0, 1.5, and 2.0 SD from the mean on tests administered are presented. RESULTS: Means were generally average across domains; however, scores ranged widely across subjects within each domain. The highest rate of deficits was observed in fine-motor speed/dexterity. Slightly higher frequencies of impairment were observed in attention and memory as compared to processing speed and verbal fluency. Results did not suggest a clear association between cognitive problems and depression or medication use but did suggest that fatigue may impact cognitive functioning. CONCLUSIONS: This study is the first to document cognitive deficits in pediatric TM and raises questions regarding our understanding of the central nervous system (CNS) injury associated with TM. Findings warrant further exploration of neuropsychological outcomes in TM to inform appropriate intervention.
Multiple Sclerosis 11/2012; · 4.26 Impact Factor
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Benjamin M Greenberg,
Laura Balcer,
Peter A Calabresi,
Bruce Cree,
Anne Cross,
Teresa Frohman,
Ralf Gold,
Eva Havrdova,
Bernhard Hemmer,
Bernd C Kieseier,
Robert Lisak,
Aaron Miller,
Michael K Racke,
Lawrence Steinman,
Olaf Stuve,
Heinz Wiendl, Elliot Frohman
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ABSTRACT: CONTEXT: Interferon beta is widely prescribed to treat multiple sclerosis (MS); however, its relationship with disability progression has yet to be established. OBJECTIVE: To investigate the association between interferon beta exposure and disability progression in patients with relapsing-remitting MS. DESIGN, SETTING, AND PATIENTS: Retrospective cohort study based on prospectively collected data (1985-2008) from British Columbia, Canada. Patients with relapsing-remitting MS treated with interferon beta (n = 868) were compared with untreated contemporary (n = 829) and historical (n = 959) cohorts. MAIN OUTCOME MEASURES: The main outcome measure was time from interferon beta treatment eligibility (baseline) to a confirmed and sustained score of 6 (requiring a cane to walk 100 m; confirmed at >150 days with no measurable improvement) on the Expanded Disability Status Scale (EDSS) (range, 0-10, with higher scores indicating higher disability). A multivariable Cox regression model with interferon beta treatment included as a time-varying covariate was used to assess the hazard of disease progression associated with interferon beta treatment. Analyses also included propensity score adjustment to address confounding by indication. RESULTS: The median active follow-up times (first to last EDSS measurement) were as follows: for the interferon beta-treated cohort, 5.1 years (interquartile range [IQR], 3.0-7.0 years); for the contemporary control cohort, 4.0 years (IQR, 2.1-6.4 years); and for the historical control cohort, 10.8 years (IQR, 6.3-14.7 years). The observed outcome rates for reaching a sustained EDSS score of 6 were 10.8%, 5.3%, and 23.1% in the 3 cohorts, respectively. After adjustment for potential baseline confounders (sex, age, disease duration, and EDSS score), exposure to interferon beta was not associated with a statistically significant difference in the hazard of reaching an EDSS score of 6 when either the contemporary control cohort (hazard ratio, 1.30; 95% CI, 0.92-1.83; P = .14) or the historical control cohort (hazard ratio, 0.77; 95% CI, 0.58-1.02; P = .07) were considered. Further adjustment for comorbidities and socioeconomic status, where possible, did not change interpretations, and propensity score adjustment did not substantially change the results. CONCLUSION: Among patients with relapsing-remitting MS, administration of interferon beta was not associated with a reduction in progression of disability.
Archives of neurology 11/2012; · 6.31 Impact Factor
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ABSTRACT: Neuromyelitis optica (NMO) is an autoimmune condition that predominantly causes severe optic neuritis and transverse myelitis. Rituximab therapy has dramatically improved patient care, but standardized dosing regimens and guidelines are lacking.
The objective of this study was to define a rituximab dosing strategy for NMO patients that achieves the lowest rate of relapses.
This was a retrospective chart review of patients treated with various doses of rituximab.
Combining data from the NMO and multiple sclerosis (MS) patients, identified that the mean number of days after a 100 mg dose of rituximab until the CD19 population was greater than 2% was 99 days (standard deviation 36, range 43-172). When allowed to rise, the mean number of days after a 1000 mg dose of rituximab until the CD19 population was greater than 2% was 184 (standard deviation 72, range 52-288). The median number of days until a CD19 percentage of 2% was achieved was 133 days in the 100 mg dosing arm and 259 days in the 1000 mg dosing arm. Analysis of the survival curves via both the Mantel-Cox log-rank test and the Wilcoxon test determined that the difference between medial survival for 100 and 1000 mg doses was statistically significant with p-values <0.0001.
Low doses of rituximab have a high rate of early B-cell repopulation. Any NMO patient treated with rituximab should be followed with monthly CD19 counts in order to identify the rare, but clinically significant, early repopulators.
Multiple Sclerosis 01/2012; 18(7):1022-6. · 4.26 Impact Factor
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Ken Sakaie,
Masaya Takahashi,
Ivan Dimitrov,
Osamu Togao,
Scott Davis,
Gina Remington,
Amy Conger,
Darrel Conger,
Teresa Frohman,
Robert Fox, Elliot Frohman
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ABSTRACT: The medial longitudinal fasciculus (MLF) is a white matter pathway in the brainstem that plays a key role in coordinating eye movements. Injury to the MLF leads to abnormalities in eye movements that can be measured with high precision by oculography, making it an ideal eloquent pathway to study imaging/function correlates. Tractography is an emerging method for identifying white matter pathways and offers the tantalizing promise of noninvasive, quantitative characterization of tissue integrity underlying functional deficits. However, the small caliber of the MLF and partial volume averaging with signal from nearby cerebrospinal fluid pose severe technical challenges to tractography-based delineation of the MLF. We discuss progress toward the goal of imaging the MLF and potential benefits of achieving this goal. Initial work suggests that ultra-high field (7 tesla) may complement tractography for characterizing the MLF.
Annals of the New York Academy of Sciences 09/2011; 1233:307-12. · 3.15 Impact Factor
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ABSTRACT: Optical coherence tomography (OCT) is a noninvasive tool used for measuring tissue at micrometer resolution. It has been extensively applied to ocular pathologies and is now being studied as a biomarker in various neurologic conditions. The retina represents a unique environment for study, with unmyelinated axons that directly synapse into the central nervous system. When trying to quantify axonal degradation in neurologic disease, the currently used imaging modalities are limited in sensitivity and specificity. Early data suggest that several neurologic conditions have pathologic changes in the retinal nerve fiber layer of the eye, creating a potential surrogate marker for neurodegeneration. OCT has the potential to become a noninvasive, reproducible test for axonal degeneration that could become an invaluable tool for measuring the efficacy of potential neuroprotective agents. If the natural history of neurodegeneration, as measured by OCT, can be documented in diseases such as Alzheimer's, Parkinson's and multiple sclerosis, then OCT can be used to measure alterations in the rate of degeneration when treatment is applied. Thus, OCT represents a new, promising technology for documenting outcomes in neuroprotection trials.
Therapeutic Advances in Neurological Disorders 05/2010; 3(3):153-60.
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ABSTRACT: Multiple sclerosis is the most common disabling neurologic disease affecting young adults and adolescents in the United States. The first objective of this article is to familiarize nonspecialists with the cardinal features of multiple sclerosis and our current understanding of its etiology, epidemiology, and natural history. The second objective is to explain the approach to diagnosis. The third is to clarify current evidence-based treatment strategies and their roles in disease modification. The overall goal is to facilitate the timely evaluation and confirmation of diagnosis and enhance effective management through collaboration among primary physicians, neurologists, and other care providers who are confronted with these formidably challenging patients.
The Medical clinics of North America 04/2009; 93(2):451-76, ix-x. · 2.18 Impact Factor
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ABSTRACT: Diffusion tensor imaging (DTI) characterizes multiple sclerosis (MS) tissue injury, although it has remained unproven whether DTI changes in disease have functional consequences. The medial longitudinal fasciculus (MLF) is a key brainstem pathway for ocular adduction and is commonly injured in patients with MS, typically resulting in internuclear ophthalmoparesis.
To validate DTI as a physiologically relevant measure of brain tissue integrity.
A correlation study of ocular dysmotility and DTI conducted between January 2004 and September 2004.
Multiple Sclerosis Center, University of Texas Southwestern Medical Center, Dallas. Patients Six patients with chronic, unilateral, or bilateral internuclear ophthalmoparesis and 10 healthy control subjects. Main Outcome Measure We used infrared oculography to correlate the velocity versional dysconjugacy index, defined as the ratio of the velocity of the abducting to adducting eye movements during horizontal saccades, and DTI measures within the MLF as measured through an anatomical overlay. Overall diffusion was measured by mean diffusivity, and anisotropy was measured by the lattice index.
Within the pontine MLF, the mean diffusivity was increased compared with healthy controls (P < .005), whereas the pontine lattice index was decreased (P < .03). Correlations were observed between the velocity versional dysconjugacy index and the mean diffusivity (left: r = 0.65, P < .01; right: r = 0.46, P = .07). Similar correlations were found between the versional dysconjugacy index and the lattice index (left: r = -0.43, P = .09; right: r = -0.65, P <.01).
We identified DTI evidence of pathologic disruption of a small brainstem fiber pathway, which is crucial for accurate horizontal eye movements. In this small study, we observed correlations between the DTI changes and oculomotor dysfunction. Our preliminary observations provide criterion validity of DTI as a surrogate marker of brain tissue integrity.
Archives of neurology 09/2008; 65(9):1179-84. · 6.31 Impact Factor
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ABSTRACT: The alpha(4) integrin antagonist natalizumab was shown to be effective in patients with immune-mediated disorders but was unexpectedly associated with JC polyomavirus associated progressive multifocal leukoencephalopathy (PML) in two multiple sclerosis (MS) and one Crohn's disease patients. Impaired immune surveillance due to natalizumab treatment may have contributed to the JCV reactivation. As HHV-6 has been suggested to play a role in MS, we asked whether this virus could also have been reactivated during natalizumab therapy. Matched sera and CSF from a limited set of MS patients treated with and without natalizumab were examined for evidence of HHV-6. In addition, we also superinfected a persistent JC virus infected glial cell with HHV-6A to determine if JC virus can be increased. Elevated serum HHV6 IgG and HHV-6A DNA was detected in the CSF of a subset of patients but not controls. We confirmed that superinfection with HHV-6 of a JC virus infected glial cells increased expression of JCV. These results support the hypothesis that treatment with natalizumab may be associated with reduced immune surveillance resulting in reactivation of viruses associated with MS pathogenesis.
PLoS ONE 02/2008; 3(4):e2028. · 4.09 Impact Factor
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ABSTRACT: Stanley Prusiner was the first to promote the concept of misfolded proteins as a cause for neurological disease. It has since been shown by him and other investigators that the scrapie isoform of prion protein (PrP(Sc)) functions as an infectious agent in numerous human and non-human disorders of the central nervous system (CNS). Interestingly, other organ systems appear to be less affected, and do not appear to lead to major co-morbidities. The physiological function of the endogenous cellular form of the prion protein (PrP(C)) is much less clear. It is intriguing that PrP(c) is expressed on most tissues in mammals, suggesting not only biological functions outside the CNS, but also a role other than the propagation of its misfolded isotype. In this review, we summarize accumulating in vitro and in vivo evidence regarding the physiological functions of PrP(C) in the nervous system, as well as in lymphoid organs.
Journal of the Neurological Sciences 02/2008; 264(1-2):1-8. · 2.35 Impact Factor
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ABSTRACT: Optic neuritis (ON), a common manifestation of multiple sclerosis (MS), often occurs as the initial manifestation of central nervous system demyelination or develops during the course of this disease. Since the retinal nerve fiber layer (RNFL) is composed only of unmyelinated axons, measuring RNFL thickness represents a viable method of monitoring axonal loss in these patients. Optical coherence tomography (OCT) is a noninvasive, noncontact, accurate, and reproducible technique that quantitates the thickness of the peripapillary RNFL, fovea, and macula. Because of its potential role in defining axonal loss in ON and in assessing longitudinal changes in the RNFL before and after MS treatment, a multidisciplinary expert panel was charged with the following tasks: assess the current capabilities of OCT; review the current data about OCT, ON, and MS; and determine whether OCT could be a primary or secondary outcome measure in future MS clinical trials. The panel concluded that: [1] OCT is valid and reproducible; [2] OCT has yielded some important limited data concerning cross-sectional studies with ON and MS; [3] more studies are required to correlate OCT results with other measures of MS disease activity; [4] after correlation with these other measures and upon agreement of standardized technical and statistical methods, OCT may evolve into a important primary or secondary outcome metric for MS clinical trials and patient care.
Journal of the Neurological Sciences 01/2008; 263(1-2):3-14. · 2.35 Impact Factor
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ABSTRACT: To outline the scientific rationale for combination therapy in multiple sclerosis and to discuss the evidence for combination treatment strategies from animal models and clinical trials of multiple sclerosis.
Experiments conducted in experimental autoimmune encephalomyelitis have recently shown beneficial effects of numerous combination therapies. The combination of approved and experimental drugs and two or more experimental agents may positively impact clinical disease activity, inflammation within the central nervous system, and neurorepair. Clinical trials are currently underway to establish the therapeutic efficacy and safety of various combination therapies for multiple sclerosis patients.
More effective therapies are needed to treat multiple sclerosis. There are good scientific rationales for the use of combination therapy in multiple sclerosis, and the pharmacologic principles for evaluating and understanding their actions are available. The evaluation of specific combination therapies in the controlled setting of clinical trials should be a priority in clinical multiple sclerosis research.
Current Opinion in Neurology 07/2007; 20(3):281-5. · 4.94 Impact Factor
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ABSTRACT: Elevated intravesical pressures secondary to detrusor sphincter dyssynergia result in an increased risk of renal deterioration in patients with cervical and thoracic spinal cord injury, although the risk is less clear in patients with multiple sclerosis (MS). The purpose of this study was to study the impact of a closed bladder outlet on intravesical pressures in patients with MS.
The data from all patients with MS referred for urologic evaluation were prospectively entered into a urodynamic database. Patients were advised to undergo full multichannel urodynamic studies. Among the patients with detrusor overactivity, the detrusor pressures were compared between the patients with and without bladder outlet dyssynergia (BOD).
Of the 143 patients referred for evaluation and entered into the database, 127 were women. Of the 127 women, 108 completed the urodynamic studies. Overall, 62 (57%) of the 108 women had detrusor overactivity, 30 of whom had coexisting BOD. The detrusor pressures during bladder contractions were greater in patients with BOD, although not significantly. For example, the maximal detrusor pressure (49.9 +/- 19.5 cm H2O versus 43.7 +/- 23.0 cm H2O, P = 0.25) and detrusor pressure at maximal flow (37.9 +/- 15.7 cm H2O versus 33.5 +/- 16.3 cm H2O, P = 0.93) were both only slightly greater in patients with BOD.
Nonsignificant elevations in detrusor pressures were noted in patients with MS and BOD. The lack of significant elevations in detrusor pressure among the patients with MS, detrusor overactivity, and BOD could account for the relatively low incidence of upper tract damage in women with MS.
Urology 06/2007; 69(5):893-7. · 2.43 Impact Factor
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ABSTRACT: We re-engineered the immunoglobulin rearrangements from clonally expanded CSF B cells of three Multiple Sclerosis patients as Fab fragments, and used three methods to test for their antigen (Ag) specificity. Nine out of ten Fab fragments were reactive to Myelin Basic Protein (MBP). The one Fab that did not react to MBP was a product of receptor editing. Two of the nine MBP reactive Fabs were also reactive to GFAP and CNPase, indicating that these clones were polyreactive. Targeting the mechanisms that allow these self-reactive B cells to reside in the CSF of MS patients may prove to be a potent immunotherapeutic strategy.
Journal of Neuroimmunology 06/2007; 186(1-2):164-76. · 2.96 Impact Factor
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ABSTRACT: Previous findings from our laboratory demonstrated that some clonally expanded cerebrospinal fluid (CSF) B cells from MS patients exhibit diminished mutation targeting patterns in comparison to typical B cells selected in the context of germinal centers (GCs). In order to determine whether the overall CSF B cell repertoires adhered to mutation patterns typical of GC-selected B cells, we analyzed the immunoglobulin repertoires from CSF B cells of 8 MS patients for mutation characteristics typical of GC-derived B cells. Mutation targeting was preserved. Thus, clonal expansion of some CSF B cells may occur independently of GC, but the CSF B cell pool is governed by typical GC selection. Interestingly, the heavy chain CDR3's of CSF B cells from MS patients had a net acidic charge, similar to GC-derived B cells, but a tendency towards longer CDR3's, consistent with autoreactive B cells. How these findings may support current hypotheses regarding the origin of CSF B cells is discussed.
Journal of Neuroimmunology 03/2007; 183(1-2):189-99. · 2.96 Impact Factor
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ABSTRACT: We do not have currently satisfactory clinical and anatomical correlates to gauge disability in multiple sclerosis. Structural biomarkers (such as MRI) are hindered because they cannot precisely segregate demyelination from axonal elements of tissue injury within the CNS. Axonal degeneration in multiple sclerosis is related to irreversible disability, which suggests that the confirmation of neuroprotective strategies needs highly quantifiable measures of axon loss that can be correlated with reliable measures of physiological function. The coupling of quantifiable measures of visual function with ocular imaging techniques, such as optical coherence tomography, enables us to begin to understand how structural changes in the visual system influence function in patients with multiple sclerosis. In this review, we consider the usefulness of optical imaging of the retina as a biomarker for neurodegeneration in multiple-sclerosis.
The Lancet Neurology 11/2006; 5(10):853-63. · 23.46 Impact Factor
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ABSTRACT: To determine the incidence of upper tract abnormalities on renal ultrasonography in patients with multiple sclerosis (MS) referred for urologic evaluation, as well as to identify any risk factors present on the basis of the historical information and urodynamic findings.
Data were derived from all patients with MS referred to the neurourology clinic during a 4-year period. The database was specifically queried for patients found to have upper tract abnormalities on screening renal ultrasonography. Demographic parameters, as well as laboratory values (creatinine) and urodynamic results, were evaluated for risk factors associated with abnormal upper tract findings.
Of the 113 patients referred and evaluated, 66 completed both urodynamic testing and renal ultrasonography. Eleven (16.7%) had abnormal ultrasound findings, with focal caliectasis the most common finding. No demographic parameter (age, sex, time since MS diagnosis, MS pattern) was associated with a greater likelihood of abnormal renal ultrasonography on univariate analysis. Neither serum creatinine nor any urodynamic finding (including the presence of dyssynergia or the threshold and amplitude of detrusor overactivity) was associated with abnormal renal ultrasound findings.
No patients in our series had any indication of obstructive uropathy more severe than mild hydronephrosis. Of the 16.7% of patients with any abnormal findings, most were noted to have minor caliectasis, likely to be of little clinical significance. Although no factors identifying patients at risk of renal abnormalities at presentation were found, ongoing evaluation of patients with baseline findings will serve to identify those at risk of progression.
Urology 06/2005; 65(5):854-7. · 2.43 Impact Factor
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Primary Care Clinics in Office Practice 04/2004; 31(1):201-26. · 1.01 Impact Factor
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J Theodore Phillips,
George Rice, Elliot Frohman,
Luc Vande Gaer,
Thomas Scott,
Judith Haas,
Eric Eggenberger,
Mark S Freedman,
William Stuart,
Luis Cunha,
Lawrence Jacobs,
Joel Oger,
Douglas Arnold,
T Jock Murray,
Mary DiBiase,
Vijay Jethwa,
Susan Goelz
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ABSTRACT: A new liquid formulation of Avonex (interferon beta-1a [IFNbeta-1a]) in a prefilled syringe has been developed to make administration of the drug easier for patients with multiple sclerosis (MS). This formulation does not contain human serum albumin (HSA), often added to interferon (IFN) products for stabilization. However, formulation changes may alter the secondary, tertiary, and quaternary structures of IFNbeta products. These kinds of structural changes could lead to the formation of antibodies directed against IFNbeta. Some of these anti-IFN antibodies may neutralize the biologic activity of IFNbeta.
This study was designed to determine the immunogenicity and safety of the new prefilled syringe (liquid) HSA-free formulation of Avonex in patients with relapsing MS.
This was a multicenter, single-arm, open-label study. Patients with relapsing MS received liquid, HSA-free Avonex 30 microg by IM injection from a prefilled syringe once weekly for up to 24 months. Immunogenicity and safety were assessed every 3 months. Serum levels of neutralizing antibodies (NAbs) were measured at baseline and every 3 months using a 2-step enzyme-linked immunosorbent assay and antiviral cytopathic effect assay.
A total of 153 patients (121 women, 32 men; mean [SD] age, 39.6 [9.9] years; age range, 19.0-59.0 years) were enrolled in the study. Sera were available for analysis from 125 and 119 patients after 18 and 24 months of treatment, respectively. By 18 months, 1 patient (1%) had > or =2 consecutive titers of > or =20, a level at which the persistent presence of NAbs has been shown in some studies to have clinical consequences. By 24 months, 1 additional patient (total 2%) had > or =2 consecutive titers of > or =20. At 18 months, 5 patients (4%) had > or =1 NAb titer of > or =5; at 24 months, 6 patients (5%) had > or =1 NAb titer of > or =5. The safety profile of liquid Avonex was comparable to the lyophilized form containing HSA.
The prefilled syringe (liquid) HSA-free formulation of Avonex was well tolerated and showed a low level of immunogenicity. Over 24 months, 2% of patients developed persistent NAbs (> or =2 consecutive titers of > or =20).
Clinical Therapeutics 04/2004; 26(4):511-21. · 2.32 Impact Factor
