Exploring the implementation of an SMS-based digital health tool on maternal and infant health in informal settlements.

BACKGROUND: The rapid urbanization of Kenya has led to an increase in the growth of informal settlements. There are challenges with access to maternal, newborn, and child health (MNCH) services and higher maternal mortality rates in settlements. The Kuboresha Afya Mitaani (KAM) study aimed to improve access to MNCH services. We evaluate one component of the KAM study, PROMPTS (Promoting Mothers through Pregnancy and Postpartum), an innovative digital health intervention aimed at improving MNCH outcomes. PROMPTS is a two-way AI-enabled SMS-based platform that sends messages to pregnant and postnatal mothers based on pregnancy stage, and connects mothers with a clinical help desk to respond and refer urgent cases in minutes. METHODS: PROMPTS was rolled out in informal settlements in Mathare and Kawangware in Nairobi County. The study adopted a pre-post intervention design, comparing baseline and endline population outcomes (1,416 participants, Baseline = 678, Endline = 738). To further explore PROMPTS's effect, outcomes were compared between endline participants enrolled and not enrolled in PROMPTS (738 participants). Outcomes related to antenatal (ANC) and postnatal (PNC) service uptake and knowledge were assessed using univariate and multivariate linear and logistic regression. RESULTS: Between baseline and enldine, mothers were 1.85 times more likely to report their babies and 1.88 times more likely to report themselves being checked by a provider post-delivery. There were improvements in moms and babies receiving care on time. 45% of the 738 endline participants were enrolled in the PROMPTS program, with 87% of these participants sending at least one message to the system. Enrolled mothers were 2.28 times more likely to report completing four or more ANC visits relative to unenrolled mothers. Similarly, enrolled mothers were 4.20 times more likely to report their babies and 1.52 times more likely to report themselves being checked by a provider post-delivery compared to unenrolled mothers. CONCLUSIONS: This research demonstrates that a digital health tool can be used to improve care-seeking and knowledge levels among pregnant and postnatal women in informal settlements. Additional research is needed to refine and target solutions amongst those that were less likely to enroll in PROMPTS and to further drive improved MNCH outcomes amongst this population.

Expanding Access to Perinatal Depression Treatment in Kenya Through Automated Psychological Support: Development and Usability Study.

BACKGROUND: Depression during pregnancy and in the postpartum period is associated with poor outcomes for women and their children. Although effective interventions exist for common mental disorders that occur during pregnancy and the postpartum period, most cases in low- and middle-income countries go untreated because of a lack of trained professionals. Task-sharing models such as the Thinking Healthy Program have shown potential in feasibility and efficacy trials as a strategy for expanding access to treatment in low-resource settings; however, there are significant barriers to scale-up. We address this gap by adapting Thinking Healthy for automated delivery via a mobile phone. This new intervention, Healthy Moms, uses an existing artificial intelligence system called Tess (Zuri in Kenya) to drive conversations with users. OBJECTIVE: This prepilot study aims to gather preliminary data on the Healthy Moms perinatal depression intervention to learn how to build and test a more robust service. METHODS: We conducted a single-case experimental design with pregnant women and new mothers recruited from public hospitals outside of Nairobi, Kenya. We invited these women to complete a brief, automated screening delivered via text messages to determine their eligibility. Enrolled participants were randomized to a 1- or 2-week baseline period and then invited to begin using Zuri. We prompted participants to rate their mood via SMS text messaging every 3 days during the baseline and intervention periods, and we used these preliminary repeated measures data to fit a linear mixed-effects model of response to treatment. We also reviewed system logs and conducted in-depth interviews with participants to study engagement with the intervention, feasibility, and acceptability. RESULTS: We invited 647 women to learn more about Zuri: 86 completed our automated SMS screening and 41 enrolled in the study. Most of the enrolled women submitted at least 3 mood ratings (31/41, 76%) and sent at least 1 message to Zuri (27/41, 66%). A third of the sample engaged beyond registration (14/41, 34%). On average, women who engaged post registration started 3.4 (SD 3.2) Healthy Moms sessions and completed 3.1 (SD 2.9) of the sessions they started. Most interviewees who tried Zuri reported having a positive attitude toward the service and expressed trust in Zuri. They also attributed positive life changes to the intervention. We estimated that using this alpha version of Zuri may have led to a 7% improvement in mood. CONCLUSIONS: Zuri is feasible to deliver via SMS and was acceptable to this sample of pregnant women and new mothers. The results of this prepilot study will serve as a baseline for future studies in terms of recruitment, data collection, and outcomes. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/11800.

A Short Message Service (SMS) increases postpartum care-seeking behavior and uptake of family planning of mothers in peri-urban public facilities in Kenya.

BACKGROUND: It is estimated that one third of maternal deaths in Kenya in 2014 could have been prevented by more timely care-seeking. Mobile health interventions are increasingly being recognized as tools for the delivery of health education and promotion. Many maternal deaths occur in the first few weeks after delivery and mothers who are given adequate care in the postpartum period have better health outcomes. Kiambu County, Kenya has a high level of literacy and phone ownership amongst mothers delivering in public hospitals and was chosen as a site for a postpartum short message service intervention. METHODS: Women were recruited after delivery and randomized to receive a package of mobile messages or standard of care only. Messages covered danger signs, general postpartum topics, and family planning. Endline phone surveys were conducted at 8 weeks postpartum to assess knowledge, care seeking behavior and family planning uptake. Analysis was conducted using Stata and is presented in odds ratios. RESULTS: Women who received the danger sign messages were 1.6 times more likely to be able to list at least 1 danger sign and 3.51 times more likely to seek treatment if they experienced postpartum danger signs. There was no significant difference in routine postpartum care seeking or care seeking behaviors concerning newborns. Women who received family planning messages were 1.85 times more likely to uptake family planning services compared to controls and 2.1 times more likely to choose a long-acting method. CONCLUSIONS: Simple, low-cost mobile interventions can support women in the early postpartum period when the information is targeted to particular points in the postpartum continuum. Additional research is needed to understand the interplay between healthcare providers and mobile health interventions. Health policy makers should consider direct mobile interventions for women as an option for supporting positive maternal health outcomes in certain populations.

Implementation of the INTERGROWTH-21st gestational dating and fetal and newborn growth standards in Nairobi, Kenya: women's experiences with ultrasound and newborn assessment.

BACKGROUND: In order to make further gains in preventing newborn deaths, effective interventions are needed. Ultrasounds and newborn anthropometry are proven interventions to identify preterm birth complications, the leading cause of newborn deaths. The INTERGROWTH-21st global gestational dating and fetal and newborn growth standards prescribe optimal growth in any population. Jacaranda Health in Kenya was the first low-resource health facility to implement the standards and evaluate their feasibility and acceptability. OBJECTIVE: To capture patients' perceptions of ultrasound and newborn care before and during implementation of the INTERGROWTH-21st standards. METHODS: The study was conducted over two years before and during the introduction of the INTERGROWTH-21st standards. Fifty pregnant and/or newly delivered women were selected for in-depth interviews and focus group discussions using convenience and purposive sampling. Interviews were conducted by research assistants using semi-structured guides once in the pre-implementation phase and twice in the implementation phase. Interviews were transcribed, double-coded by two independent researchers and thematically analyzed together. Demographic information was obtained from hospital records. RESULTS: Patients reported being generally satisfied with ultrasound care when providers communicated effectively. Women reported a priority for ultrasound was that it allowed them to feel reassured. However, a clear need for better pre-screening information emerged consistently from patients. Women noted that factors facilitating their choosing to have an ultrasound included ensuring the well-being of the fetus and learning the sex. Barriers included wait times and financial constraints. Patients were generally satisfied with care using the newborn standards. CONCLUSIONS: As the INTERGROWTH-21st standards are implemented worldwide, understanding ways to facilitate implementation is critical. Increased and standardized communication about ultrasound should be provided before the procedure to increase satisfaction and uptake. Considering patient perspectives when integrating new standards or guidelines into routine clinical care will inform effective strategies in care provision, thus improving maternal and newborn health and survival.

Expanding Access to Depression Treatment in Kenya Through Automated Psychological Support: Protocol for a Single-Case Experimental Design Pilot Study.

BACKGROUND: Depression during pregnancy and in the postpartum period is associated with a number of poor outcomes for women and their children. Although effective interventions exist for common mental disorders that occur during pregnancy and the postpartum period, most cases in low- and middle-income countries go untreated because of a lack of trained professionals. Task-sharing models such as the Thinking Healthy Program have shown great potential in feasibility and efficacy trials as a strategy for expanding access to treatment in low-resource settings, but there are significant barriers to scale-up. We are addressing this gap by adapting Thinking Healthy for automated delivery via a mobile phone. This new intervention, Healthy Moms, uses an existing artificial intelligence system called Tess (Zuri in Kenya) to drive conversations with users. OBJECTIVE: The objective of this pilot study is to test the Healthy Moms perinatal depression intervention using a single-case experimental design with pregnant women and new mothers recruited from public hospitals outside of Nairobi, Kenya. METHODS: We will invite patients to complete a brief, automated screening delivered via text messages to determine their eligibility. Enrolled participants will be randomized to a 1- or 2-week baseline period and then invited to begin using Zuri. Participants will be prompted to rate their mood via short message service every 3 days during the baseline and intervention periods. We will review system logs and conduct in-depth interviews with participants to study engagement with the intervention, feasibility, and acceptability. We will use visual inspection, in-depth interviews, and Bayesian estimation to generate preliminary data about the potential response to treatment. RESULTS: Our team adapted the intervention content in April and May 2018 and completed an initial prepilot round of formative testing with 10 women from a private maternity hospital in May and June. In preparation for this pilot study, we used feedback from these users to revise the structure and content of the intervention. Recruitment for this protocol began in early 2019. Results are expected toward the end of 2019. CONCLUSIONS: The main limitation of this pilot study is that we will recruit women who live in urban and periurban centers in one part of Kenya. The results of this study may not generalize to the broader population of Kenyan women, but that is not an objective of this phase of work. Our primary objective is to gather preliminary data to know how to build and test a more robust service. We are working toward a larger study with a more diverse population. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/11800.

Implementing the INTERGROWTH-21st gestational dating and fetal and newborn growth standards in peri-urban Nairobi, Kenya: Provider experiences, uptake and clinical decision-making.

BACKGROUND: Perinatal and newborn complications are major risk factors for unfavorable fetal and neonatal outcomes. Gestational dating and growth monitoring can be instrumental in the identification and management of high-risk pregnancies and births. The INTERGROWTH-21st Project developed the first global standards for gestational dating and fetal and newborn growth monitoring, supplying a toolkit for clinicians. This study aimed to assess the feasibility and acceptability of the first known implementation study of these standards in a low resource setting. METHODS: The study was performed in two 12-month phases from March 2016 to March 2018 at Jacaranda Health, a private maternity hospital in peri-urban Nairobi, Kenya. In-depth interviews, focus group discussions and a provider survey were utilized to evaluate providers' experiences during implementation. Client chart data, for pregnant women attending antenatal care and/or delivering at Jacaranda Health along with their newborns, were captured to assess uptake and effect of the standards on clinical decision-making. RESULTS: Facility-level support and provider buy-in proved to be critical factors driving the success of implementing the standards. However, additional support was needed to strengthen capacity to conduct and interpret ultrasounds and maintain motivation among providers. We observed a significant increase in the uptake of obstetric ultrasounds, particularly gestational dating, during the implementation of the standards. Although no significant changes were detected in the identification of high-risk pregnancies, referrals and deliveries by Cesarean section during implementation, we did observe a significant reduction in inductions for post-date. No significant barriers were reported regarding the use of the newborn standards. Over 80% of providers advocated for the standards to remain in place with some enhancements related mainly to training, advocacy and procurement. CONCLUSIONS: The findings are timely with increasing global adoption of the standards and the challenging and multi-faceted nature of translating new, evidence-based guidelines into routine clinical practice.

Leveraging tuberculosis case relative locations to enhance case detection and linkage to care in Swaziland.

BACKGROUND: In Swaziland, as in many high HIV/TB burden settings, there is not information available regarding the household location of TB cases for identifying areas of increased TB incidence, limiting the development of targeted interventions. Data from "Butimba", a TB REACH active case finding project, was re-analyzed to provide insight into the location of TB cases surrounding Mbabane, Swaziland. OBJECTIVE: The project aimed to identify geographical areas with high TB burdens to inform active case finding efforts. METHODS: Butimba implemented household contact tracing; obtaining landmark based, informal directions, to index case homes, defined here as relative locations. The relative locations were matched to census enumeration areas (known location reference areas) using the Microsoft Excel Fuzzy Lookup function. Of 403 relative locations, an enumeration area reference was detected in 388 (96%). TB cases in each census enumeration area and the active case finders in each Tinkhundla, a local governmental region, were mapped using the geographic information system, QGIS 2.16. RESULTS: Urban Tinkhundla predictably accounted for most cases; however, after adjusting for population, the highest density of cases was found in rural Tinkhundla. There was no correlation between the number of active case finders currently assigned to the 7 Tinkhundla surrounding Mbabane and the total number of TB cases (Spearman rho = -0.57, p = 0.17) or the population adjusted TB cases (Spearman rho = 0.14, p = 0.75) per Tinkhundla. DISCUSSION: Reducing TB incidence in high-burden settings demands novel analytic approaches to study TB case locations. We demonstrated the feasibility of linking relative locations to more precise geographical areas, enabling data-driven guidance for National Tuberculosis Programs' resource allocation. In collaboration with the Swazi National Tuberculosis Control Program, this analysis highlighted opportunities to better align the active case finding national strategy with the TB disease burden.

Full-length and fragmented netrin-1 in multiple sclerosis plaques are inhibitors of oligodendrocyte precursor cell migration.

Oligodendrocytes exhibit a limited capacity to remyelinate in multiple sclerosis. Factors present in multiple sclerosis lesions are thought to inhibit oligodendrocyte precursor cell migration, limiting their recruitment to axons requiring remyelination; however, few inhibitors have been identified. A candidate inhibitor is netrin-1, a secreted protein that repels migrating oligodendrocyte precursor cells during neural development and is expressed by myelinating oligodendrocytes in the mature rodent central nervous system. Herein, we examined the distribution of netrin-1 in adult human white matter and multiple sclerosis lesions. We detected full-length netrin-1 protein and shorter netrin-1 fragments in samples of normal white matter and of multiple sclerosis lesions from adult human brain. We demonstrate that peptides corresponding to amino terminal domains VI and V of netrin-1 repel migrating oligodendrocyte precursor cells, but lack the chemoattractant activity of full-length netrin-1. Furthermore, recombinant domains VI-V of netrin-1 disrupt the chemoattractant activity of full-length netrin-1, consistent with a competitive mechanism of action. These findings indicate that full-length and fragmented forms of netrin-1, found in multiple sclerosis lesions, have the capacity to inhibit oligodendrocyte precursor migration, identifying netrin-1 as a potential target for therapies that promote remyelination.

A condensed performance-validation strategy for multiplex detection kits used in studies of human clinical samples.

Quantification of soluble phase analytes represents one of the most commonly used techniques applied to a broad range of samples in both basic and clinical immunology laboratories, as well as in context of drug development and diagnostic programs. The recent increase in the application of multiplex immunoassays, such as Luminex, has resulted in a growing array of commercially available multiplex kits. Validated, highly sensitive, and precise methods for such quantification is critical, especially when applied to precious sample collections. While vendors are expected to carry out kit performance validation, discrepancies between technical specifications provided with multiplex kits and their actual performance can be relatively common. Here we present a validation strategy that will aid users to select the optimal kits for their purpose and most validly interpret results from the multiplex assays. To illustrate key considerations when validating and comparing kits, we assess the performance of three conventional multiplex cytokine kits. Our findings confirm the importance of validating the performance of commercial multiplex kits and provide a practical and cost-effective approach that can be readily implemented in both academic and translational laboratory settings.

Implication of perturbed axoglial apparatus in early pediatric multiple sclerosis.

Cerebrospinal fluid samples collected from children during initial presentation of central nervous system inflammation, who may or may not subsequently be diagnosed as having multiple sclerosis (MS), were subjected to large-scale proteomics screening. Unexpectedly, major compact myelin membrane proteins typically implicated in MS were not detected. However, multiple molecules that localize to the node of Ranvier and the surrounding axoglial apparatus membrane were implicated, indicating perturbed axon-glial interactions in those children destined for diagnosis of MS.

From bench to MS bedside: challenges translating biomarker discovery to clinical practice.

A substantial need exists for developing and validating a range of biomarkers that would address a number of important unmet clinical needs in the MS field. In spite of considerable efforts over last years, very few putative biomarkers have been fully validated or successfully integrated into routine clinical practice. Here, we consider some of the main challenges that have limited such effective translation from biomarker discovery to the bedside in the context of MS, the prototypic chronic human CNS inflammatory illness. We will define the types of biomarkers that would be relevant for MS, identify their ideal attributes, and then discuss individual challenges and strategies to overcome them.

Secretory products of multiple sclerosis B cells are cytotoxic to oligodendroglia in vitro.

B cells are important in the pathogenesis of multiple sclerosis (MS) and some of the effects are not dependent on maturation of B cells into immunoglobulin (Ig) producing plasmablasts and plasma cells. B cells present antigen, activate T cells, and are involved in immunoregulation and cytokine secretion. To determine if B cells from MS patients secrete products that have deleterious effects on glial cells not mediated by Ig, and to compare effects with secretory products of normal controls (NC), we isolated B cells from 7 patients with relapsing remitting MS (RRMS) and 4 NC. B cells were cultured alone or after stimulation with CD40 ligand (CD40L), CD40L+cross-linking of the B cell antigen receptor (xBCR) and CD40L+xBCR+stimulation of toll like receptor 9 (TLR9). Supernatants were harvested and incubated with mixed central nervous system (CNS) neonatal rat glial cells. Supernatants from unstimulated NC B cells induced on average death of 7% (range 0-24%) of differentiated oligodendrocytes (OL); in contrast, supernatants from unstimulated B cells from RRMS patients induced death of 57% (range 35-74%) of OL. Supernatants of stimulated B cells from NC did not increase the minimal OL death whereas stimulation of B cells from RRMS had variable results compared to unstimulated B cells. Supernatants from both NC and RRMS induced microglial enlargement and loss of normal resting bipolar morphology. OL death did not correlate with levels of tumor necrosis alpha (TNF-α), lymphotoxin alpha (LT-α), interleukin 6 (IL-6), IL-10, transforming growth factor beta 1 (TGF-ß1) or any combination or ratio of these cytokines. Analysis of 26 supernatants from NC and RRMS patients failed to detect IgM. There were very low levels of IgG in 8 of the 26 supernatants, and no correlation between of OL death and presence or absence of IgG. Sera used in both the B cell and glial cell cultures were heated, which inactivates complement. The effects of B cell supernatants on OL could be direct and/or indirect involving either microglia and/or astrocytes. The identity of the toxic factor(s) is as yet unknown. Thus we have demonstrated that B cells from patients with RRMS but not NC secrete one or more factors toxic to OL. It is possible that such factors produced by peripheral blood B cells when within the CNS could contribute to demyelination in MS patients.

A central role for RhoA during oligodendroglial maturation in the switch from netrin-1-mediated chemorepulsion to process elaboration.

The guidance cue netrin-1 and its receptor Deleted in Colorectal Cancer play distinct roles during different stages of oligodendrocyte development. A gradient of netrin-1 repels migrating oligodendrocyte precursor cells (OPCs) in the embryonic spinal cord by promoting process collapse, but later in development netrin-1 increases oligodendrocyte process extension and branching. Here we investigate the intracellular mechanism that governs this switch in response to netrin-1, and focus on the role of the GTPase RhoA and its effector Rho Kinase (ROCK) downstream of netrin-1 in OPCs and maturing oligodendrocytes. In OPCs, we show that netrin-1 induces a sustained increase in RhoA activity that requires Deleted in Colorectal Cancer function. Furthermore, we demonstrate that activation of RhoA and ROCK is required for the reduction in OPC process length triggered by netrin-1, and for the chemorepellent response made by OPCs to netrin-1. Unlike OPCs, application of netrin-1 to oligodendrocytes decreases RhoA activity. We demonstrate that inactivation of RhoA is essential for netrin-1 to increase oligodendrocyte process branching. We conclude that netrin-1 induces distinct morphological responses in OPCs and oligodendrocytes through differential regulation of RhoA activity.

The netrin protein family.

The name netrin is derived from the Sanskrit Netr, meaning 'guide'. Netrins are a family of extracellular proteins that direct cell and axon migration during embryogenesis. Three secreted netrins (netrins 1, 3 and 4), and two glycosylphosphatidylinositol (GPI)-anchored membrane proteins, netrins G1 and G2, have been identified in mammals. The secreted netrins are bifunctional, acting as attractants for some cell types and repellents for others. Receptors for the secreted netrins include the Deleted in Colorectal Cancer (DCC) family, the Down's syndrome cell adhesion molecule (DSCAM), and the UNC-5 homolog family: Unc5A, B, C and D in mammals. Netrin Gs do not appear to interact with these receptors, but regulate synaptic interactions between neurons by binding to the transmembrane netrin G ligands NGL1 and 2. The chemotropic function of secreted netrins has been best characterized with regard to axon guidance during the development of the nervous system. Extending axons are tipped by a flattened, membranous structure called the growth cone. Multiple extracellular guidance cues direct axonal growth cones to their ultimate targets where synapses form. Such cues can be locally derived (short-range), or can be secreted diffusible cues that allow target cells to signal axons from a distance (long-range). The secreted netrins function as short-range and long-range guidance cues in different circumstances. In addition to directing cell migration, functional roles for netrins have been identified in the regulation of cell adhesion, the maturation of cell morphology, cell survival and tumorigenesis.

Netrin 1 and Dcc regulate oligodendrocyte process branching and membrane extension via Fyn and RhoA.

The molecular mechanisms underlying the elaboration of branched processes during the later stages of oligodendrocyte maturation are not well understood. Here we describe a novel role for the chemotropic guidance cue netrin 1 and its receptor deleted in colorectal carcinoma (Dcc) in the remodeling of oligodendrocyte processes. Postmigratory, premyelinating oligodendrocytes express Dcc but not netrin 1, whereas mature myelinating oligodendrocytes express both. We demonstrate that netrin 1 promotes process extension by premyelinating oligodendrocytes in vitro and in vivo. Addition of netrin 1 to mature oligodendrocytes in vitro evoked a Dcc-dependent increase in process branching. Furthermore, expression of netrin 1 and Dcc by mature oligodendrocytes was required for the elaboration of myelin-like membrane sheets. Maturation of oligodendrocyte processes requires intracellular signaling mechanisms involving Fyn, focal adhesion kinase (FAK), neuronal Wiscott-Aldrich syndrome protein (N-WASP) and RhoA; however, the extracellular cues upstream of these proteins in oligodendrocytes are poorly defined. We identify a requirement for Src family kinase activity downstream of netrin-1-dependent process extension and branching. Using oligodendrocytes derived from Fyn knockout mice, we demonstrate that Fyn is essential for netrin-1-induced increases in process branching. Netrin 1 binding to Dcc on mature oligodendrocytes recruits Fyn to a complex with the Dcc intracellular domain that includes FAK and N-WASP, resulting in the inhibition of RhoA and inducing process remodeling. These findings support a novel role for netrin 1 in promoting oligodendrocyte process branching and myelin-like membrane sheet formation. These essential steps in oligodendroglial maturation facilitate the detection of target axons, a key step towards myelination.

Maintenance of axo-oligodendroglial paranodal junctions requires DCC and netrin-1.

Paranodal axoglial junctions are essential for the segregation of myelinated axons into distinct domains and efficient conduction of action potentials. Here, we show that netrin-1 and deleted in colorectal cancer (DCC) are enriched at the paranode in CNS myelin. We then address whether netrin-1 signaling influences paranodal adhesion between oligodendrocytes and axons. In the absence of netrin-1 or DCC function, oligodendroglial paranodes initially develop and mature normally but later become disorganized. Lack of DCC or netrin-1 resulted in detachment of paranodal loops from the axonal surface and the disappearance of transverse bands. Furthermore, the domain organization of myelin is compromised in the absence of netrin-1 signaling: K+ channels inappropriately invade the paranodal region, and the normally restricted paranodal distribution of Caspr expands longitudinally along the axon. Our findings identify an essential role for netrin-1 and DCC regulating the maintenance of axoglial junctions.

Simvastatin regulates oligodendroglial process dynamics and survival.

Simvastatin, a lipophilic statin that crosses the blood-brain barrier, is being evaluated as a potential therapy for multiple sclerosis (MS) due to its anti-inflammatory properties. We assessed the effects of simvastatin on cultures of rat newborn and human fetal oligodendrocyte progenitor cells (OPCs) and human adult mature oligodendrocytes (OLGs) with respect to cellular events pertaining to myelin maintenance and repair. Short-term simvastatin treatment of OPCs (1 day) induced robust process extension, enhanced differentiation to a mature phenotype, and decreased spontaneous migration. These effects were reversed by isoprenoid products and mimicked with an inhibitor of Rho kinase (ROCK), the downstream effector of the isoprenylated protein RhoA GTPase. Prolonged treatment (2 days) caused process retraction that was rescued by cholesterol, and increased cell death (4 days) partially rescued by either cholesterol or isoprenoid co-treatment. In comparison, simvastatin treatment of human mature OLGs required a longer initial time course (2 days) to induce significant process outgrowth, mimicked by inhibiting ROCK. Prolonged treatment of mature OLGs was associated with process retraction (6 days) and increased cell death (8 days). Human-derived OPCs and mature OLGs demonstrated an increased sensitivity to simvastatin relative to the rodent cells, responding to nanomolar versus micromolar concentrations. Our findings indicate the importance of considering the short- and long-term effects of systemic immunomodulatory therapies on neural cells affected by the MS disease process. (c) 2006 Wiley-Liss, Inc.