Interleukin 4 is important in protective immunity to a gastrointestinal nematode infection in mice.

Parasitic helminths typically induce components of immediate-type hypersensitivity, including elevated serum IgE, eosinophilia, and mucosal mast cells. These responses are T-cell-dependent and associated with rapid expulsion of parasitic worms from a sensitized host; existing experimental systems have failed to define the precise role of cytokines in these responses. We report here that anti-interleukin 4 or anti-interleukin 4 receptor antibodies block the polyclonal IgE response to a parasitic nematode, Heligmosomoides polygyrus, and abrogate protective immunity to the infection. In contrast, anti-interleukin 5 antibody prevented H. polygyrus-induced eosinophilia but did not prevent protection. These data provide evidence that a specific cytokine affects the physiology and survival of a parasitic nematode in the host.     

Immunolocalisation of fibrillin microfibrils in the calf metacarpal and vertebral growth plate

Overgrowth of limbs and spinal deformities are typical clinical manifestations of Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCA), caused by mutations of the genes encoding fibrillin‐1 (FBN1) and fibrillin‐2 (FBN2), respectively. FBN1 mutations are also associated with acromicric (AD) and geleophysic dysplasias (GD), and with Weill–Marchesani syndrome (WMS), which is characterised by short stature. The mechanisms leading to such abnormal skeletal growth and the involvement of the fibrillins are not understood. Postnatal longitudinal bone growth mainly occurs in the epiphyseal growth plate. Here we investigated the organisation of fibrillin microfibrils in the growth plate of the long bone and vertebra immunohistochemically. Fibrillin‐1 was dual‐immunostained with elastin, with fibrillin‐2 or with collagen X. We report that fibrillin microfibrils are distributed throughout all regions of the growth plate, and that fibrillin‐1 and fibrillin‐2 were differentially organised. Fibrillin‐1 was more abundant in the extracellular matrix of the resting and proliferative zones of the growth plate than in the hypertrophic zone. More fibrillin‐2 was found in the calcified region than in the other regions. No elastin fibres were observed in either the proliferative or hypertrophic zones. This study indicates that, as fibrillin microfibrils are involved in growth factor binding and may play a mechanical role, they could be directly involved in regulating bone growth. Hence, mutations of the fibrillins could affect their functional role in growth and lead to the growth disorders seen in patients with MFS, CCA, AD, GD and WMS.     

Head Impact Exposure in Youth Football: High School Ages 14 to 18 Years and Cumulative Impact Analysis

Sports-related concussion is the most common athletic head injury with football having the highest rate among high school athletes. Traditionally, research on the biomechanics of football-related head impact has been focused at the collegiate level. Less research has been performed at the high school level, despite the incidence of concussion among high school football players. The objective of this study is to twofold: to quantify the head impact exposure in high school football, and to develop a cumulative impact analysis method. Head impact exposure was measured by instrumenting the helmets of 40 high school football players with helmet mounted accelerometer arrays to measure linear and rotational acceleration. A total of 16,502 head impacts were collected over the course of the season. Biomechanical data were analyzed by team and by player. The median impact for each player ranged from 15.2 to 27.0 g with an average value of 21.7 (±2.4) g. The 95th percentile impact for each player ranged from 38.8 to 72.9 g with an average value of 56.4 (±10.5) g. Next, an impact exposure metric utilizing concussion injury risk curves was created to quantify cumulative exposure for each participating player over the course of the season. Impacts were weighted according to the associated risk due to linear acceleration and rotational acceleration alone, as well as the combined probability (CP) of injury associated with both. These risks were summed over the course of a season to generate risk weighted cumulative exposure. The impact frequency was found to be greater during games compared to practices with an average number of impacts per session of 15.5 and 9.4, respectively. However, the median cumulative risk weighted exposure based on combined probability was found to be greater for practices vs. games. These data will provide a metric that may be used to better understand the cumulative effects of repetitive head impacts, injury mechanisms, and head impact exposure of athletes in football.     

Mapping default mode connectivity alterations following a single season of subconcussive impact exposure in youth football

Repetitive head impact (RHI) exposure in collision sports may contribute to adverse neurological outcomes in former players. In contrast to a concussion, or mild traumatic brain injury, “subconcussive” RHIs represent a more frequent and asymptomatic form of exposure. The neural network‐level signatures characterizing subconcussive RHIs in youth collision‐sport cohorts such as American Football are not known. Here, we used resting‐state functional MRI to examine default mode network (DMN) functional connectivity (FC) following a single football season in youth players (n = 50, ages 8–14) without concussion. Football players demonstrated reduced FC across widespread DMN regions compared with non‐collision sport controls at postseason but not preseason. In a subsample from the original cohort (n = 17), players revealed a negative change in FC between preseason and postseason and a positive and compensatory change in FC during the offseason across the majority of DMN regions. Lastly, significant FC changes, including between preseason and postseason and between in‐ and off‐season, were specific to players at the upper end of the head impact frequency distribution. These findings represent initial evidence of network‐level FC abnormalities following repetitive, non‐concussive RHIs in youth football. Furthermore, the number of subconcussive RHIs proved to be a key factor influencing DMN FC.     

A randomized trial of two postexposure prophylaxis regimens to reduce mother-to-child HIV-1 transmission in infants of untreated mothers

BACKGROUND: Single-dose nevirapine (NVP) prophylaxis to mother and infant is widely used in resource-constrained settings for preventing mother-to-child transmission (MTCT) of HIV-1. Where women do not access antenatal care or HIV testing, postexposure prophylaxis to the infant may be an important preventative strategy. METHODS: This multicentre, randomized, open-label clinical trial (October 2000 to September 2002) in South Africa compared single-dose NVP with 6 weeks of zidovudine (ZDV), commenced within 24 h of delivery among 1051 infants whose mothers had no prior antiretroviral therapy. HIV-1 infection rates were ascertained at birth, and at 6 and 12 weeks of age. Kaplan-Meier survival methods were used to estimate HIV-1 infection rates in an intention-to-treat analysis. RESULTS: Overall, 6 week and 12 week MTCT probability was 12.8% [95% confidence interval (CI),10.5-15.0] and 16.3% (95% CI,13.4-19.2), respectively. At 12 weeks, among infants who were not infected at birth, 24 (7.9%) infections occurred in the NVP arm and 41 (13.1%) in the ZDV arm (log rank P = 0.06). Using multivariate analysis, factors associated with infection following birth were ZDV use [odds ratio (OR), 1.8; 95% CI,1.1-3.2; P = 0.032), maternal CD4 cell count < 500 x 10(6) cells/l (OR, 2.5; 95% CI,1.3-5.0; P = 0.007), maternal viral load > 50 000 copies/ml (OR, 3.6; 95% CI,2.0-6.2; P < 0.0001) and breastfeeding (OR, 2.2; 95% CI,1.3-3.8; P = 0.006). CONCLUSION: A single-dose of NVP given to infants offers protection against HIV-1 infection and should be a strategy used in infants of mothers with untreated HIV infection.     

Premature pubarche: etiological heterogeneity.

Premature pubarche is characterized by pubic hair, adult type body odor, acne, and axillary hair before 8 yr of age in girls and 9.5 yr of age in boys. Causes of this premature virilization include premature adrenarche, mild errors of steroidogenesis, precocious puberty, and adrenal and gonadal tumors. To determine whether any clinical parameters are helpful in distinguishing which children should undergo further evaluation for mild congenital adrenal hyperplasia, we performed ACTH stimulation tests in 69 children with premature pubarche and 8 pubertal controls. Patients were categorized as having typical (pubic hair with or without axillary hair and body odor) or atypical (pubic hair and genital enlargement) premature pubarche. Blood samples, before and 30 min after iv bolus administration of synthetic ACTH, were obtained for progesterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, dehydroepiandrosterone, androstenedione, 11-deoxycortisol, and cortisol measurements. The patients were divided into 4 groups based on their individual responses to ACTH stimulation: premature adrenarche (no apparent defect in steroidogenesis), possible decreased 21-hydroxylase activity, possible decreased 3 beta-hydroxysteroid dehydrogenase activity, and indeterminate responses. Five of 11 (45%) children with atypical premature pubarche and 7 of 58 (12%) children with typical premature pubarche were found to have evidence of mild defects in steroidogenesis. Similar to previous reports in postpubertal women, only responses to ACTH stimulation allowed accurate classification of these patients.     

Chronic colitis is associated with a reduction of mucosal alkaline sphingomyelinase activity

BACKGROUND AND AIMS: The hydrolysis of sphingomyelin (SM) generates key molecules regulating cell growth. Animal cancer studies support an inhibitory role for this pathway in the malignant transformation of the colonic mucosa. The activity of a specific intestinal alkaline sphingomyelinase (SMase), which hydrolyzes SM, is reduced in colorectal tumors. In this study we measured alkaline SMase activity in patients with longstanding colitis and assessed if a reduction can be used as a marker in surveillance of high risk patients. METHODS: Alkaline SMase activity was measured in 139 colonic biopsies from 34 patients with longstanding, extensive colitis and from 11 controls. Fifteen patients had earlier diagnosis of dysplasia or DNA aneuploidy. Alkaline SMase activity was related to histologic dysplasia and DNA aneuploidy assessed by flow cytometry, patient age, and duration of disease. RESULTS: Alkaline SMase activity was significantly lower in the patient group with and without dysplasia compared with controls (p = 0.006). In biopsies, an association was not found between alkaline SMase activity, dysplasia, or DNA ploidy. However, alkaline SMase activity decreased with age both in patients and controls (p = 0.008). CONCLUSIONS: Reduction of alkaline SMase activity seen in colorectal cancer and adenomas is also present in patients with chronic colitis. It is not complementary to dysplasia or DNA-aneuploidy in the identification of high risk patients. The age-associated decrease of alkaline SMase activity seems to be a general phenomenon indicating premature senescence of the mucosa in longstanding colitis.     

The normal cellular prion protein is strongly expressed by myeloid dendritic cells.

Abnormal isoforms of the prion protein (PrP(Sc)) that cause prion diseases are propagated and spread within the body by "carrier" cell(s). Cells of the immune system have been strongly implicated in this process. In particular, PrP(Sc) is known to accumulate on follicular dendritic cells (FDCs) in individuals affected by variant Creutzfeld-Jakob disease. However, FDCs do not migrate widely and the natural history of prion disorders suggests other cells may be required for the transport of PrP(Sc) from the site of ingestion to lymphoid organs and the central nervous system. Substantial evidence suggests that the spread of PrP(Sc) requires bone marrow-derived cells that express normal cellular prion protein (PrP(C)). This study examined the expression of PrP(C) on bone marrow-derived cells that interact with lymphoid follicles. High levels of PrP(C) are present on myeloid dendritic cells (DCs) that surround the splenic white pulp. These myeloid DCs are ontologically and functionally distinct from the FDCs. Consistent with these observations, expression of PrP(C) was strongly induced during the generation of mature myeloid DCs in vitro. In these cells PrP(C) colocalized with major histocompatibility complex class II molecules at the level of light microscopy. Furthermore, given the close anatomic and functional connection of myeloid DCs with lymphoid follicles, these results raise the possibility that myeloid DCs may play a role in the propagation of PrP(Sc) in humans.