Safety, pharmacokinetics, and antiretroviral activity of multiple doses of ibalizumab (formerly TNX-355), an anti-CD4 monoclonal antibody in HIV-1 infected adults

Context: Despite tremendous strides in HIV treatment over the past decade, resistance remains a major problem. A growing number of patients develop resistance and require new therapies to suppress viral replication. ^ Objective: To assess the safety of multiple administrations of the anti-CD4 receptor (anti-CD4) monoclonal antibody ibalizumab given as intravenous (IV) infusions, in three dosage regimens, in subjects infected with human immunodeficiency virus (HIV-1). ^ Design: Phase 1, multi-center, open-label, randomized clinical trial comparing the safety, pharmacokinetics and antiviral activity of three dosages of ibalizumab. ^ Setting: Six clinical trial sites in the United States. ^ Participants: A total of twenty-two HIV-positive patients on no anti-retroviral therapy or a stable failing regimen. ^ Intervention: Randomized to one of two treatment groups in Arms A and B followed by non-randomized enrollment in Arm C. Patients randomized to Arm A received 10 mg/kg of ibalizumab every 7 days, for a total of 10 doses; patients randomized to Arm B received a total of six doses of ibalizumab; a single loading dose of 10 mg/kg on Day 1 followed by five maintenance doses of 6 mg/kg every 14 days, starting at Week 1. Patients assigned to Arm C received 25 mg/kg of ibalizumab every 14 days for a total of 5 doses. All patients were followed for safety for an additional 7 to 8 weeks. ^ Main Outcome Measures: Clinical and laboratory assessments of safety and tolerability of multiple administrations of ibalizumab in HIV-infected patients. Secondary measures of efficacy include HIV-1 RNA (viral load) measurements. ^ Results: 21 patients were treatment-experienced and 1 was naïve to HIV therapy. Six patients were failing despite therapy and 15 were on no current HIV treatment. Mean baseline viral load (4.78 log 10; range 3.7-5.9) and CD4+ cell counts (332/μL; range 89-494) were similar across cohorts. Mean peak decreases in viral load from baseline of 0.99 log10(1.11 log10, and 0.96 log 10 occurred by Wk 2 in Cohorts A, B and C, respectively. Viral loads decreased by >1.0 log10 in 64%; 4 patients viral loads were suppressed to < 400 copies/mL. Viral loads returned towards baseline by Week 9 with reduced susceptibility to ibalizumab. CD4+ cell counts rose transiently and returned toward baseline. Maximum median elevations above BL in CD4+ cell counts for Cohorts A, B and C were +257, +198 and +103 cells/μL, respectively and occurred within 3 Wks in 16 of 22 subjects. The half-life of ibalizumab was 3-3.5 days and elimination was characteristic of capacity-limited kinetics. Administration of ibalizumab was well tolerated. Four serious adverse events were reported during the study. None of these events were related to study drug. Headache, nausea and cough were the most frequently reported treatment emergent adverse events and there were no laboratory abnormalities related to study drug. ^ Conclusions: Ibalizumab administered either weekly or bi-weekly was safe, well tolerated, and demonstrated antiviral activity. Further studies with ibalizumab in combination with standard antiretroviral treatments are warranted.^

FEMALE SEXUAL MATURATION AND BLOOD PRESSURE (SECONDARY-SEX CHARACTERISTICS, GROWTH, DEVELOPMENT)

This study described the relationship of sexual maturation and blood pressure in a sample (n = 361) of white females, ages seven through 18, attending public schools in a defined area of Central Texas during October through December, 1984. Other correlates of blood pressure were also described for this sample.^ A survey was performed to obtain the data on height, weight, body mass, pulse rate, upper arm circumference and length, and blood pressure. Each subject self-assessed her secondary sex characteristics (breast and pubic hair) according to drawings of the Tanner stages of maturation. The subjects were interviewed to obtain data on personal health habits and menstrual status. Student age, ethnic group and place of residence were abstracted from school records. Parents or guardians of the subjects responded to a questionnaire pertaining to parental and subject health history and parents' occupation and educational attainment.^ In the simple linear regression analysis, sexual maturation and variables of body size were significantly (p < 0.001) and positively associated with systolic and fourth- and fifth-phase diastolic blood pressure. The demographic and socioeconomic variables were not sufficiently variant in this population to have differential effects on the relation between blood pressure and maturation. Stepwise multiple regression was used to assess the contribution of sexual maturation to the variance of blood pressure after accounting for the variables of body size. Sexual maturation (breast stage) along with weight, height and body mass remained in the multiple regression models for fourth- and fifth-phase diastolic blood pressure. Only height and body mass remained in the regression model for systolic blood pressure; sexual maturation did not contribute more to the explanation of the systolic blood pressure variance.^ The association of sexual maturation with blood pressure level was established in this sample of young white females. More research is needed first, to determine if this relationship prevails in other populations of young females, and second, to determine the relationship of sexual maturation sequence and change with the change of blood pressure during childhood and adolescence. ^

Motivational interviewing and feedback for college drinkers: Handling missing values with complete case analysis and multiple imputation

Objective: In this secondary data analysis, three statistical methodologies were implemented to handle cases with missing data in a motivational interviewing and feedback study. The aim was to evaluate the impact that these methodologies have on the data analysis. ^ Methods: We first evaluated whether the assumption of missing completely at random held for this study. We then proceeded to conduct a secondary data analysis using a mixed linear model to handle missing data with three methodologies (a) complete case analysis, (b) multiple imputation with explicit model containing outcome variables, time, and the interaction of time and treatment, and (c) multiple imputation with explicit model containing outcome variables, time, the interaction of time and treatment, and additional covariates (e.g., age, gender, smoke, years in school, marital status, housing, race/ethnicity, and if participants play on athletic team). Several comparisons were conducted including the following ones: 1) the motivation interviewing with feedback group (MIF) vs. the assessment only group (AO), the motivation interviewing group (MIO) vs. AO, and the intervention of the feedback only group (FBO) vs. AO, 2) MIF vs. FBO, and 3) MIF vs. MIO.^ Results: We first evaluated the patterns of missingness in this study, which indicated that about 13% of participants showed monotone missing patterns, and about 3.5% showed non-monotone missing patterns. Then we evaluated the assumption of missing completely at random by Little's missing completely at random (MCAR) test, in which the Chi-Square test statistic was 167.8 with 125 degrees of freedom, and its associated p-value was p=0.006, which indicated that the data could not be assumed to be missing completely at random. After that, we compared if the three different strategies reached the same results. For the comparison between MIF and AO as well as the comparison between MIF and FBO, only the multiple imputation with additional covariates by uncongenial and congenial models reached different results. For the comparison between MIF and MIO, all the methodologies for handling missing values obtained different results. ^ Discussions: The study indicated that, first, missingness was crucial in this study. Second, to understand the assumptions of the model was important since we could not identify if the data were missing at random or missing not at random. Therefore, future researches should focus on exploring more sensitivity analyses under missing not at random assumption.^

Multiple Input-Output Bidirectional Solid State Transformer Based on a Series Resonant Converter

Las fuentes de alimentación de modo conmutado (SMPS en sus siglas en inglés) se utilizan ampliamente en una gran variedad de aplicaciones. La tarea más difícil para los diseñadores de SMPS consiste en lograr simultáneamente la operación del convertidor con alto rendimiento y alta densidad de energía. El tamaño y el peso de un convertidor de potencia está dominado por los componentes pasivos, ya que estos elementos son normalmente más grandes y más pesados que otros elementos en el circuito. Para una potencia de salida dada, la cantidad de energía almacenada en el convertidor que ha de ser entregada a la carga en cada ciclo de conmutación, es inversamente proporcional a la frecuencia de conmutación del convertidor. Por lo tanto, el aumento de la frecuencia de conmutación se considera un medio para lograr soluciones más compactas con los niveles de densidad de potencia más altos. La importancia de investigar en el rango de alta frecuencia de conmutación radica en todos los beneficios que se pueden lograr: además de la reducción en el tamaño de los componentes pasivos, el aumento de la frecuencia de conmutación puede mejorar significativamente prestaciones dinámicas de convertidores de potencia. Almacenamiento de energía pequeña y el período de conmutación corto conducen a una respuesta transitoria del convertidor más rápida en presencia de las variaciones de la tensión de entrada o de la carga. Las limitaciones más importantes del incremento de la frecuencia de conmutación se relacionan con mayores pérdidas del núcleo magnético convencional, así como las pérdidas de los devanados debido a los efectos pelicular y proximidad. También, un problema potencial es el aumento de los efectos de los elementos parásitos de los componentes magnéticos - inductancia de dispersión y la capacidad entre los devanados - que causan pérdidas adicionales debido a las corrientes no deseadas. Otro factor limitante supone el incremento de las pérdidas de conmutación y el aumento de la influencia de los elementos parásitos (pistas de circuitos impresos, interconexiones y empaquetado) en el comportamiento del circuito. El uso de topologías resonantes puede abordar estos problemas mediante el uso de las técnicas de conmutaciones suaves para reducir las pérdidas de conmutación incorporando los parásitos en los elementos del circuito. Sin embargo, las mejoras de rendimiento se reducen significativamente debido a las corrientes circulantes cuando el convertidor opera fuera de las condiciones de funcionamiento nominales. A medida que la tensión de entrada o la carga cambian las corrientes circulantes incrementan en comparación con aquellos en condiciones de funcionamiento nominales. Se pueden obtener muchos beneficios potenciales de la operación de convertidores resonantes a más alta frecuencia si se emplean en aplicaciones con condiciones de tensión de entrada favorables como las que se encuentran en las arquitecturas de potencia distribuidas. La regulación de la carga y en particular la regulación de la tensión de entrada reducen tanto la densidad de potencia del convertidor como el rendimiento. Debido a la relativamente constante tensión de bus que se encuentra en arquitecturas de potencia distribuidas los convertidores resonantes son adecuados para el uso en convertidores de tipo bus (transformadores cc/cc de estado sólido). En el mercado ya están disponibles productos comerciales de transformadores cc/cc de dos puertos que tienen muy alta densidad de potencia y alto rendimiento se basan en convertidor resonante serie que opera justo en la frecuencia de resonancia y en el orden de los megahercios. Sin embargo, las mejoras futuras en el rendimiento de las arquitecturas de potencia se esperan que vengan del uso de dos o más buses de distribución de baja tensión en vez de una sola. Teniendo eso en cuenta, el objetivo principal de esta tesis es aplicar el concepto del convertidor resonante serie que funciona en su punto óptimo en un nuevo transformador cc/cc bidireccional de puertos múltiples para atender las necesidades futuras de las arquitecturas de potencia. El nuevo transformador cc/cc bidireccional de puertos múltiples se basa en la topología de convertidor resonante serie y reduce a sólo uno el número de componentes magnéticos. Conmutaciones suaves de los interruptores hacen que sea posible la operación en las altas frecuencias de conmutación para alcanzar altas densidades de potencia. Los problemas posibles con respecto a inductancias parásitas se eliminan, ya que se absorben en los Resumen elementos del circuito. El convertidor se caracteriza con una muy buena regulación de la carga propia y cruzada debido a sus pequeñas impedancias de salida intrínsecas. El transformador cc/cc de puertos múltiples opera a una frecuencia de conmutación fija y sin regulación de la tensión de entrada. En esta tesis se analiza de forma teórica y en profundidad el funcionamiento y el diseño de la topología y del transformador, modelándolos en detalle para poder optimizar su diseño. Los resultados experimentales obtenidos se corresponden con gran exactitud a aquellos proporcionados por los modelos. El efecto de los elementos parásitos son críticos y afectan a diferentes aspectos del convertidor, regulación de la tensión de salida, pérdidas de conducción, regulación cruzada, etc. También se obtienen los criterios de diseño para seleccionar los valores de los condensadores de resonancia para lograr diferentes objetivos de diseño, tales como pérdidas de conducción mínimas, la eliminación de la regulación cruzada o conmutación en apagado con corriente cero en plena carga de todos los puentes secundarios. Las conmutaciones en encendido con tensión cero en todos los interruptores se consiguen ajustando el entrehierro para obtener una inductancia magnetizante finita en el transformador. Se propone, además, un cambio en los señales de disparo para conseguir que la operación con conmutaciones en apagado con corriente cero de todos los puentes secundarios sea independiente de la variación de la carga y de las tolerancias de los condensadores resonantes. La viabilidad de la topología propuesta se verifica a través una extensa tarea de simulación y el trabajo experimental. La optimización del diseño del transformador de alta frecuencia también se aborda en este trabajo, ya que es el componente más voluminoso en el convertidor. El impacto de de la duración del tiempo muerto y el tamaño del entrehierro en el rendimiento del convertidor se analizan en un ejemplo de diseño de transformador cc/cc de tres puertos y cientos de vatios de potencia. En la parte final de esta investigación se considera la implementación y el análisis de las prestaciones de un transformador cc/cc de cuatro puertos para una aplicación de muy baja tensión y de decenas de vatios de potencia, y sin requisitos de aislamiento. Abstract Recently, switch mode power supplies (SMPS) have been used in a great variety of applications. The most challenging issue for designers of SMPS is to achieve simultaneously high efficiency operation at high power density. The size and weight of a power converter is dominated by the passive components since these elements are normally larger and heavier than other elements in the circuit. If the output power is constant, the stored amount of energy in the converter which is to be delivered to the load in each switching cycle is inversely proportional to the converter’s switching frequency. Therefore, increasing the switching frequency is considered a mean to achieve more compact solutions at higher power density levels. The importance of investigation in high switching frequency range comes from all the benefits that can be achieved. Besides the reduction in size of passive components, increasing switching frequency can significantly improve dynamic performances of power converters. Small energy storage and short switching period lead to faster transient response of the converter against the input voltage and load variations. The most important limitations for pushing up the switching frequency are related to increased conventional magnetic core loss as well as the winding loss due to the skin and proximity effect. A potential problem is also increased magnetic parasitics – leakage inductance and capacitance between the windings – that cause additional loss due to unwanted currents. Higher switching loss and the increased influence of printed circuit boards, interconnections and packaging on circuit behavior is another limiting factor. Resonant power conversion can address these problems by using soft switching techniques to reduce switching loss incorporating the parasitics into the circuit elements. However the performance gains are significantly reduced due to the circulating currents when the converter operates out of the nominal operating conditions. As the input voltage or the load change the circulating currents become higher comparing to those ones at nominal operating conditions. Multiple Input-Output Many potential gains from operating resonant converters at higher switching frequency can be obtained if they are employed in applications with favorable input voltage conditions such as those found in distributed power architectures. Load and particularly input voltage regulation reduce a converter’s power density and efficiency. Due to a relatively constant bus voltage in distributed power architectures the resonant converters are suitable for bus voltage conversion (dc/dc or solid state transformation). Unregulated two port dc/dc transformer products achieving very high power density and efficiency figures are based on series resonant converter operating just at the resonant frequency and operating in the megahertz range are already available in the market. However, further efficiency improvements of power architectures are expected to come from using two or more separate low voltage distribution buses instead of a single one. The principal objective of this dissertation is to implement the concept of the series resonant converter operating at its optimum point into a novel bidirectional multiple port dc/dc transformer to address the future needs of power architectures. The new multiple port dc/dc transformer is based on a series resonant converter topology and reduces to only one the number of magnetic components. Soft switching commutations make possible high switching frequencies to be adopted and high power densities to be achieved. Possible problems regarding stray inductances are eliminated since they are absorbed into the circuit elements. The converter features very good inherent load and cross regulation due to the small output impedances. The proposed multiple port dc/dc transformer operates at fixed switching frequency without line regulation. Extensive theoretical analysis of the topology and modeling in details are provided in order to compare with the experimental results. The relationships that show how the output voltage regulation and conduction losses are affected by the circuit parasitics are derived. The methods to select the resonant capacitor values to achieve different design goals such as minimum conduction losses, elimination of cross regulation or ZCS operation at full load of all the secondary side bridges are discussed. ZVS turn-on of all the switches is achieved by relying on the finite magnetizing inductance of the Abstract transformer. A change of the driving pattern is proposed to achieve ZCS operation of all the secondary side bridges independent on load variations or resonant capacitor tolerances. The feasibility of the proposed topology is verified through extensive simulation and experimental work. The optimization of the high frequency transformer design is also addressed in this work since it is the most bulky component in the converter. The impact of dead time interval and the gap size on the overall converter efficiency is analyzed on the design example of the three port dc/dc transformer of several hundreds of watts of the output power for high voltage applications. The final part of this research considers the implementation and performance analysis of the four port dc/dc transformer in a low voltage application of tens of watts of the output power and without isolation requirements.

RB-mediated suppression of spontaneous multiple neuroendocrine neoplasia and lung metastases in Rb+/− mice

Alterations in pathways mediated by retinoblastoma susceptibility gene (RB) product are among the most common in human cancer. Mice with a single copy of the Rb gene are shown to develop a syndrome of multiple neuroendocrine neoplasia. The earliest Rb-deficient atypical cells were identified in the intermediate and anterior lobes of the pituitary, the thyroid and parathyroid glands, and the adrenal medulla within the first 3 months of postnatal development. These cells form gross tumors with various degrees of malignancy by postnatal day 350. By age of 380 days, 84% of Rb+/− mice exhibited lung metastases from C-cell thyroid carcinomas. Expression of a human RB transgene in the Rb+/− mice suppressed carcinogenesis in all tissues studied. Of particular clinical relevance, the frequency of lung metastases also was reduced to 12% in Rb+/− mice by repeated i.v. administration of lipid-entrapped, polycation-condensed RB complementary DNA. Thus, in spite of long latency periods during which secondary alterations can accumulate, the initial loss of Rb function remains essential for tumor progression in multiple types of neuroendocrine cells. Restoration of RB function in humans may prove an effective general approach to the treatment of RB-deficient disseminated tumors.

Three 1-Aminocyclopropane-1-Carboxylate Synthase Genes Regulated by Primary and Secondary Pollination Signals in Orchid Flowers1

The temporal and spatial expression patterns of three 1-aminocyclopropane-1-carboxylate (ACC) synthase genes were investigated in pollinated orchid (Phalaenopsis spp.) flowers. Pollination signals initiate a cascade of development events in multiple floral organs, including the induction of ethylene biosynthesis, which coordinates several postpollination developmental responses. The initiation and propagation of ethylene biosynthesis is regulated by the coordinated expression of three distinct ACC synthase genes in orchid flowers. One ACC synthase gene (Phal-ACS1) is regulated by ethylene and participates in amplification and interorgan transmission of the pollination signal, as we have previously described in a related orchid genus. Two additional ACC synthase genes (Phal-ACS2 and Phal-ACS3) are expressed primarily in the stigma and ovary of pollinated orchid flowers. Phal-ACS2 mRNA accumulated in the stigma within 1 h after pollination, whereas Phal-ACS1 mRNA was not detected until 6 h after pollination. Similar to the expression of Phal-ACS2, the Phal-ACS3 gene was expressed within 2 h after pollination in the ovary. Exogenous application of auxin, but not ACC, mimicked pollination by stimulating a rapid increase in ACC synthase activity in the stigma and ovary and inducing Phal-ACS2 and Phal-ACS3 mRNA accumulation in the stigma and ovary, respectively. These results provide the basis for an expanded model of interorgan regulation of three ACC synthase genes that respond to both primary (Phal-ACS2 and Phal-ACS3) and secondary (Phal-ACS1) pollination signals.

Goal Orientation Profiles and Self-Concept of Secondary School Students

The objective of this study is to identify possible combinations of multiple goals that lead to different goal orientation profiles and to determine whether there are significant group differences in self-concept dimensions. The Achievement Goals Tendencies Questionnaire (AGTQ) and the Self-Description Questionnaire-II (SDQ-II) were administered to a sample of 2,022 students of Compulsory Secondary education, ranging in age from 12 to 16 years (M = 13.81, SD = 1.35). Cluster analysis identified four profiles of motivational goals: a group of students with a generalized high motivation profile, a group of students with generalized low motivation profile, a group of students with a predominance of learning goals and achievement goals, and a last group of students with a predominance of achievement goals and social reinforcement goals. Results reveal statistically significant differences among the profiles obtained regarding self-concept dimensions.

Motivational profiles Spanish students of Compulsory Secondary Education: Differential analysis of academic self-attributions

Academic goals and academic self-attributions are relevant variables in school settings. The objective of this study is to identify whether there are combinations of multiple goals that lead to different motivational profiles and to determine whether there are significant differences between the groups obtained regarding causal attributions of success and failure (ability, effort, or external causes) in Mathematics and Language and Literature, and in overall academic performance. The Goal Achievement Tendencies Questionnaire (AGTQ) and the Sydney Attribution Scale (SAS) were administered to a sample of 2022 students of compulsory secondary education, ranging in age from 12 to 16 years (M = 13.81, SD = 1.35). Cluster analysis identified four motivational profiles: a group of students with a high generalized motivation profile, a group of students with low generalized motivation profile, a group of students with predominance of learning goals and achievement goals, and a final group of students with predominance of social reinforcement goals. Results revealed statistically significant differences between the profiles obtained in academic self-attributions.

Association of secondary glioblastoma and pituitary adenoma : case report

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

The Antigenic response to a booster injection of a multiple antigen preparation containing diphtheria, pertussis, and tetanus antigens given seven years or more after primary immunization /

Mode of access: Internet.

Translation of the flavivirus Kunjin NS3 gene in cis but not its RNA sequence or secondary structure is essential for efficient RNA packaging

Our previous studies using trans-complementation analysis of Kunjin virus (KUN) full-length cDNA clones harboring in-frame deletions in the NS3 gene demonstrated the inability of these defective complemented RNAs to be packaged into virus particles (W. J. Liu, P. L. Sedlak, N. Kondratieva, and A. A. Khromykh, J. Virol. 76:10766-10775). In this study we aimed to establish whether this requirement for NS3 in RNA packaging is determined by the secondary RNA structure of the NS3 gene or by the essential role of the translated NS3 gene product. Multiple silent mutations of three computer-predicted stable RNA structures in the NS3 coding region of KUN replicon RNA aimed at disrupting RNA secondary structure without affecting amino acid sequence did not affect RNA replication and packaging into virus-like particles in the packaging cell line, thus demonstrating that the predicted conserved RNA structures in the NS3 gene do not play a role in RNA replication and/or packaging. In contrast, double frameshift mutations in the NS3 coding region of full-length KUN RNA, producing scrambled NS3 protein but retaining secondary RNA structure, resulted in the loss of ability of these defective RNAs to be packaged into virus particles in complementation experiments in KUN replicon-expressing cells. Furthermore, the more robust complementation-packaging system based on established stable cell lines producing large amounts of complemented replicating NS3-deficient replicon RNAs and infection with KUN virus to provide structural proteins also failed to detect any secreted virus-like particles containing packaged NS3-deficient replicon RNAs. These results have now firmly established the requirement of KUN NS3 protein translated in cis for genome packaging into virus particles.

Multiple system atrophy: laminar distribution of the pathological changes in frontal and temporal neocortex--a study in ten patients

OBJECTIVE: To determine the distribution of the pathological changes in the neocortex in multiple-system atrophy (MSA). METHOD: The vertical distribution of the abnormal neurons (neurons with enlarged or atrophic perikarya), surviving neurons, glial cytoplasmic inclusions (GCI) and neuronal cytoplasmic inclusions (NI) were studied in alpha-synuclein-stained material of frontal and temporal cortex in ten cases of MSA. RESULTS: Abnormal neurons exhibited two common patterns of distribution, viz., density was either maximal in the upper cortex or a bimodal distribution was present with a density peak in the upper and lower cortex. The NI were either located in the lower cortex or were more uniformly distributed down the cortical profile. The distribution of the GCI varied considerably between gyri and cases. The density of the glial cell nuclei was maximal in the lower cortex in the majority of gyri. In a number of gyri, there was a positive correlation between the vertical densities of the abnormal neurons, the total number of surviving neurons, and the glial cell nuclei. The vertical densities of the GCI were not correlated with those of the surviving neurons or glial cells but the GCI and NI were positively correlated in a small number of gyri. CONCLUSION: The data suggest that there is significant degeneration of the frontal and temporal lobes in MSA, the lower laminae being affected more significantly than the upper laminae. Cortical degeneration in MSA is likely to be secondary to pathological changes occurring within subcortical areas.

Multiple system atrophy (MSA): Topographic distribution of the alpha-synuclein-associated pathological changes

To study the topographic distribution of the pathology in multiple system atrophy (MSA). Pattern analysis was carried out using a-synuclein immunohistochemistry in 10 MSA cases. The glial cytoplasmic inclusions (GCI) were distributed randomly or in large clusters. The neuronal inclusions (NI) and abnormal neurons were distributed in regular clusters. Clusters of the NI and abnormal neurons were spatially correlated whereas the GCI were not spatially correlated with either the NI or the abnormal neurons. The data suggest that the GCI represent the primary change in MSA and the neuronal pathology develops secondary to the glial pathology.