Morphometric changes at the craniocervical junction during childhood.

OBJECTIVE: Current understanding of how the pediatric craniocervical junction develops remains incomplete. Measurements of anatomical relationships at the craniocervical junction can influence clinical and surgical decision-making. The purpose of this analysis was to quantitatively define clinically relevant craniocervical junction measurements in a population of children with CT scans that show normal anatomy. METHODS: A total of 1458 eligible patients were identified from children between 1 and 18 years of age who underwent cervical spine CT scanning at a single institution. Patients were separated by both sex and age in years into 34 groups. Following this, patients within each group were randomly selected for inclusion until a target of 15 patients in each group had been reached. Each patient underwent measurement of the occipital condyle-C1 interval (CCI), pB-C2, atlantodental interval (ADI), basion-dens interval (BDI), basion-opisthion diameter (BOD), basion-axial interval (BAI), dens angulation, and canal diameter at C1. Mean values were calculated in each group. Each measurement was performed by two teams and compared for intraclass correlation coefficient (ICC). RESULTS: The data showed that CCI, ADI, BDI, and dens angulation decrease in magnitude throughout childhood, while pB-C2, PADI, BAI, and BOD increase throughout childhood, with an ICC of fair to good (range 0.413-0.912). Notably, CCI decreases continuously on coronal CT scans, whereas on parasagittal CT scans, CCI does not decrease until after age 9, when it shows a continuous decline similar to measurements on coronal CT scans. CONCLUSIONS: These morphometric analyses establish parameters for normal pediatric craniocervical spine growth for each year of life up to 18 years. The data should be considered when evaluating children for potential surgical intervention.

Outcomes and factors associated with infant abusive head trauma in the US.

OBJECT Head trauma is the leading cause of death in abused children, particularly prior to the age of 2 years. An awareness of factors associated with this condition as well as with a higher risk of mortality is important to improve outcomes and prevent the occurrence of these events. The objective of this study was to evaluate outcomes and factors associated with poor outcomes in infants with diagnosed abusive head trauma (AHT). Patient characteristics, socioeconomic factors, and secondary conditions such as retinal bleeding, contusion, and fractures were considered. METHODS Data were obtained from the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality. From the Kids' Inpatient Database (KID) sample, the authors identified infants no older than 23 months who had been diagnosed with AHT in 2000, 2003, 2006, and 2009. All statistical analyses were conducted in SAS 9.2. Descriptive statistics were provided, and multivariate logistic regression models were applied to evaluate factors associated with mortality and nonroutine discharge. RESULTS A total of 5195 infants were analyzed in this study. Most infants (85.5%) had ages ranging between 0 and 11 months and were male (61.6%). Overall mortality was 10.8%, with a rate of 9.8% in the 0- to 11-month-old cohort and 16.5% in the 12- to 23-month-olds (p = 0.0003). The overall nonroutine discharge rate of 25.6% increased significantly from 23.3% to 39.0% with increasing age (0-11 vs 12-23 months of age, p < 0.0001). Assuming a multivariate model that adjusted for multiple confounders, the authors found that older infants (12-23 vs 0-11 months, OR 1.81, 95% CI 1.18-2.77) with a secondary diagnosis of retinal bleeding (OR 2.85, 95% CI 2.02-4.00) or shaken baby syndrome (OR 2.09, 95% CI 1.48-2.94) had an increased risk of mortality; these factors were similarly associated with an increased odds of a nonroutine discharge. A higher income ($30,001-$35,000 vs $1-$24,999) was associated with a reduction in the odds of mortality (OR 0.46, 95% CI 0.29-0.72). In the subset of cases (1695 [32.6%]) that specified the perpetrator involved in infant injury, the authors found that the father, stepfather, or boyfriend was most frequently reported (67.4%). A trend for a higher AHT incidence was documented in the early ages (peak at 2 months) compared with older ages. CONCLUSIONS Despite the higher incidence of AHT among infants during the earlier months of life, higher mortality was documented in the 12- to 23-month-olds. Retinal bleeding and shaken baby syndrome were secondary diagnoses associated with higher mortality and nonroutine discharge. Males (67.4%) were overwhelmingly documented as the perpetrators involved in the injury of these infants.

Therapeutic effects of glatiramer acetate and grafted CD115⁺ monocytes in a mouse model of Alzheimer's disease.

Weekly glatiramer acetate immunization of transgenic mice modelling Alzheimer's disease resulted in retained cognition (Morris water maze test), decreased amyloid-ß plaque burden, and regulation of local inflammation through a mechanism involving enhanced recruitment of monocytes. Ablation of bone marrow-derived myeloid cells exacerbated plaque pathology, whereas weekly administration of glatiramer acetate enhanced cerebral recruitment of innate immune cells, which dampened the pathology. Here, we assessed the therapeutic potential of grafted CD115(+) monocytes, injected once monthly into the peripheral blood of transgenic APPSWE/PS1ΔE9 Alzheimer's disease mouse models, with and without weekly immunization of glatiramer acetate, as compared to glatiramer acetate alone. All immune-modulation treatment groups were compared with age-matched phosphate-buffered saline-injected control transgenic and untreated non-transgenic mouse groups. Two independent cohorts of mice were assessed for behavioural performance (6-8 mice/group); treatments started in 10-month-old symptomatic mice and spanned a total of 2 months. For all three treatments, our data suggest a substantial decrease in cognitive deficit as assessed by the Barnes maze test (P < 0.0001-0.001). Improved cognitive function was associated with synaptic preservation and reduction in cerebral amyloid-ß protein levels and astrogliosis (P < 0.001 and P < 0.0001), with no apparent additive effects for the combined treatment. The peripherally grafted, green fluorescent protein-labelled and endogenous monocytes, homed to cerebral amyloid plaques and directly engulfed amyloid-ß; their recruitment was further enhanced by glatiramer acetate. In glatiramer acetate-immunized mice and, moreover, in the combined treatment group, monocyte recruitment to the brain was coupled with greater elevation of the regulatory cytokine IL10 surrounding amyloid-ß plaques. All treated transgenic mice had increased cerebral levels of MMP9 protein (P < 0.05), an enzyme capable of degrading amyloid-ß, which was highly expressed by the infiltrating monocytes. In vitro studies using primary cultures of bone marrow monocyte-derived macrophages, demonstrated that glatiramer acetate enhanced the ability of macrophages to phagocytose preformed fibrillar amyloid-ß1-42 (P < 0.0001). These glatiramer acetate-treated macrophages exhibited increased expression of the scavenger receptors CD36 and SCARA1 (encoded by MSR1), which can facilitate amyloid-ß phagocytosis, and the amyloid-ß-degrading enzyme MMP9 (P < 0.0001-0.001). Overall, our studies indicate that increased cerebral infiltration of monocytes, either by enrichment of their levels in the circulation or by weekly immunization with glatiramer acetate, resulted in substantial attenuation of disease progression in murine Alzheimer's models by mechanisms that involved enhanced cellular uptake and enzymatic degradation of toxic amyloid-ß as well as regulation of brain inflammation.

Angiotensin-converting enzyme overexpression in myelomonocytes prevents Alzheimer's-like cognitive decline.

Cognitive decline in patients with Alzheimer's disease (AD) is associated with elevated brain levels of amyloid ß protein (Aß), particularly neurotoxic Aß(1-42). Angiotensin-converting enzyme (ACE) can degrade Aß(1-42), and ACE overexpression in myelomonocytic cells enhances their immune function. To examine the effect of targeted ACE overexpression on AD, we crossed ACE(10/10) mice, which overexpress ACE in myelomonocytes using the c-fms promoter, with the transgenic APP(SWE)/PS1(ΔE9) mouse model of AD (AD⁺). Evaluation of brain tissue from these AD⁺ACE(10/10) mice at 7 and 13 months revealed that levels of both soluble and insoluble brain Aß(1-42) were reduced compared with those in AD⁺ mice. Furthermore, both plaque burden and astrogliosis were drastically reduced. Administration of the ACE inhibitor ramipril increased Aß levels in AD⁺ACE(10/10) mice compared with the levels induced by the ACE-independent vasodilator hydralazine. Overall, AD⁺ACE(10/10) mice had less brain-infiltrating cells, consistent with reduced AD-associated pathology, though ACE-overexpressing macrophages were abundant around and engulfing Aß plaques. At 11 and 12 months of age, the AD⁺ACE(10/WT) and AD⁺ACE(10/10) mice were virtually equivalent to non-AD mice in cognitive ability, as assessed by maze-based behavioral tests. Our data demonstrate that an enhanced immune response, coupled with increased myelomonocytic expression of catalytically active ACE, prevents cognitive decline in a murine model of AD.