Alemtuzumab (anti-CD52 mAb) provides long-lasting disease activity suppression in relapsing–remitting multiple sclerosis (RRMS). The objective of this study was to characterize the immunological reconstitution of T cell subsets and its contribution to the prolonged RRMS suppression following alemtuzumab-induced lymphocyte depletion. The study was performed on blood samples from RRMS patients enrolled in the CARE-MS II clinical trial, which was recently completed and led to the submission of alemtuzumab for U.S. Food and Drug Administration approval as a treatment for RRMS. Alemtuzumab-treated patients exhibited a nearly complete depletion of circulating CD4⁺ lymphocytes at day 7. During the immunological reconstitution, CD4⁺CD25⁺CD127^low regulatory T cells preferentially expanded within the CD4⁺ lymphocytes, reaching their peak expansion at month 1. The increase in the percentage of TGF-β1–, IL-10–, and IL-4–producing CD4⁺ cells reached a maximum at month 3, whereas a significant decrease in the percentages of Th1 and Th17 cells was detected at months 12 and 24 in comparison with the baseline. A gradual increase in serum IL-7 and IL-4 and a decrease in IL-17A, IL-17F, IL-21, IL-22, and IFN-γ levels were detected following treatment. In vitro studies have demonstrated that IL-7 induced an expansion of CD4⁺CD25⁺CD127^low regulatory T cells and a decrease in the percentages of Th17 and Th1 cells. In conclusion, our results indicate that differential reconstitution of T cell subsets and selectively delayed CD4⁺ T cell repopulation following alemtuzumab-induced lymphopenia may contribute to its long-lasting suppression of disease activity.

Cortical thickness (CT) and surface area (SA) vary widely between individuals and are associated with intellectual ability and risk for various psychiatric and neurodevelopmental conditions. Factors influencing this variability remain poorly understood, but the radial unit hypothesis, as well as the more recent supragranular cortex expansion hypothesis, suggests that prenatal and perinatal influences may be particularly important. In this report, we examine the impact of 17 major demographic and obstetric history variables on interindividual variation in CT and SA in a unique sample of 805 neonates who received MRI scans of the brain around 2 weeks of age. Birth weight, postnatal age at MRI, gestational age at birth, and sex emerged as important predictors of SA. Postnatal age at MRI, paternal education, and maternal ethnicity emerged as important predictors of CT. These findings suggest that individual variation in infant CT and SA is explained by different sets of environmental factors with neonatal SA more strongly influenced by sex and obstetric history and CT more strongly influenced by socioeconomic and ethnic disparities. Findings raise the possibility that interventions aimed at reducing disparities and improving obstetric outcomes may alter prenatal/perinatal cortical development.

Individual differences in neuroanatomy are associated with intellectual ability and psychiatric risk. Factors responsible for this variability remain poorly understood. We tested whether 17 major demographic and obstetric variables were associated with individual differences in brain volumes in 756 neonates assessed with MRI. Gestational age at MRI, sex, gestational age at birth, and birthweight were the most significant predictors, explaining 31% to 59% of variance. Unexpectedly, earlier born babies had larger brains than later born babies after adjusting for other predictors. Our results suggest earlier born children experience accelerated brain growth, either as a consequence of the richer sensory environment they experience outside the womb or in response to other factors associated with delivery. In the full sample, maternal and paternal education, maternal ethnicity, maternal smoking, and maternal psychiatric history showed marginal associations with brain volumes, whereas maternal age, paternal age, paternal ethnicity, paternal psychiatric history, and income did not. Effects of parental education and maternal ethnicity are partially mediated by differences in birthweight. Remaining effects may reflect differences in genetic variation or cultural capital. In particular late initiation of prenatal care could negatively impact brain development. Findings could inform public health policy aimed at optimizing child development.

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease caused by the absence of dystrophin, a membrane-stabilizing protein encoded by theDMDgene. Although mouse models of DMD provide insight into the potential of a corrective therapy, data from genetically homologous large animals, such as the dystrophin-deficient golden retriever muscular dystrophy (GRMD) model, may more readily translate to humans. To evaluate the clinical translatability of an adeno-associated virus serotype 9 vector (AAV9)–microdystrophin (μDys5) construct, we performed a blinded, placebo-controlled study in which 12 GRMD dogs were divided among four dose groups [control, 1 × 10¹³vector genomes per kilogram (vg/kg), 1 × 10¹⁴vg/kg, and 2 × 10¹⁴vg/kg;n= 3 each], treated intravenously at 3 months of age with a canine codon-optimized microdystrophin construct, rAAV9-CK8e-c-μDys5, and followed for 90 days after dosing. All dogs received prednisone (1 milligram/kilogram) for a total of 5 weeks from day −7 through day 28. We observed dose-dependent increases in tissue vector genome copy numbers; μDys5 protein in multiple appendicular muscles, the diaphragm, and heart; limb and respiratory muscle functional improvement; and reduction of histopathologic lesions. As expected, given that a truncated dystrophin protein was generated, phenotypic test results and histopathologic lesions did not fully normalize. All administrations were well tolerated, and adverse events were not seen. These data suggest that systemically administered AAV-microdystrophin may be dosed safely and could provide therapeutic benefit for patients with DMD.