Effects of prior polysaccharide vaccination on magnitude, duration, and quality of immune responses to and safety profile of a meningococcal serogroup C tetanus toxoid conjugate vaccination in adults

Extensive use of meningococcal AC polysaccharide (MACP) vaccines has raised concerns about induction of immunologic hyporesponsiveness to C polysaccharide. We investigated the immunogenicity and safety of a meningococcal C-tetanus conjugate (MCC-TT) vaccine in naive adults and prior MACP vaccinees. Laboratory staff (n = 113) were recruited; 73 were naive to meningococcal vaccination, and 40 had previously received > or =1 dose of MACP vaccine. Blood was taken prior to MCC-TT vaccination and 1 week, 1 month, and 6 months later. At each time point, proportions of subjects with serum bactericidal antibody (SBA) titers of > or =8 or > or =128 were similar (P > 0.46); >94% of subjects achieved titers of > or =128 at 1 month. However, the geometric mean titer (GMT) of SBA at 1 month was higher in the naive (1,757; 95% confidence interval [95% CI], 1,102 to 2,803) than in the previously vaccinated (662; 95% CI, 363 to 1,207) group (P = 0.02), and similarly at 6 months (P < 0.001). Conversely, geometric mean concentrations (GMCs) of serogroup C-specific immunoglobulin G (IgG) were significantly higher in the previously vaccinated group pre-MCC-TT and at 1 week; the groups were similar at 1 month, and there was some evidence that the GMC for the previously vaccinated group was higher at 6 months. Qualitative differences in antibodies between groups were demonstrated by using the SBA/IgG ratio, though avidity measures were similar for the two groups throughout the study. MCC-TT was well tolerated, with similar safety profiles in the two groups. Pain in the arm and headache were the most frequently reported events following vaccination. The study shows that MCC-TT is safe and immunogenic in naive and previously MACP-vaccinated adults, though the magnitude and persistence of postvaccination SBA responses in the latter group were lower.     

Modulation of resistance to Salmonella typhimurium infection in mice by mouse hepatitis virus (MHV)

Prior infection of mice with a field strain of mouse hepatitis virus (MHV) increased the early resistance of euthymic mice to virulent Salmonella typhimurium strain SR-11 infections (as defined by significantly fewer salmonella colony-forming units (cfu) present in spleens and livers 4 days after salmonella infection). This increase in salmonella resistance was observed when the interval between MHV and salmonella infections was 6 days, but not at 3, 10, or 14 day intervals. The mouse Ity locus, which controls the number of intracellular salmonella, had a significant effect on the ability of MHV to induce resistance to salmonella. MHV caused an increase in resistance to salmonella in Itys (salmonella susceptible) mice at all doses of salmonella tested (100 to 10,000 cfu). In the Ityr (salmonella resistant) mice tested the beneficial effect of MHV on salmonella resistance was small and when observed, was only present at salmonella doses of 10,000 cfu or greater. Neither the Lpsd nor Xid mutations affected the ability of MHV to increase resistance to salmonella infection. In contrast to euthymic mice, MHV infection greatly decreased the resistance of athymic (nude) mice to salmonella infection. Since the Nu locus does not affect the resistance of mice to salmonella (at 4 days post salmonella infection), these results indicate that MHV infection and the nude phenotype interact to increase susceptibility to salmonella. These findings re-emphasize the importance of keeping laboratory mice used in research free of MHV and other immunomodulatory pathogens.     

Association study of a SNAP‐25 microsatellite and attention deficit hyperactivity disorder

Several lines of evidence implicate synaptosomal‐associated protein of 25 kDa (SNAP‐25) in the etiology of attention deficit hyperactivity disorder (ADHD). Most notably, the coloboma mouse mutant, considered to be a good animal model of hyperactivity, has a deletion spanning this gene. Introducing a SNAP‐25 transgene into these animals alleviates hyperlocomotion. We have identified a novel microsatellite repeat in SNAP‐25 located between the 5′UTR and the first coding exon, and tested for association with ADHD. Case‐control analyses suggest there may be a role of this polymorphism in ADHD, with one allele over‐represented in controls and another over‐represented in probands. Within‐family tests of linkage and association confirmed these findings. Further work is needed to ascertain the role of SNAP‐25 in ADHD and assess the functional significance of this polymorphism. © 2002 Wiley‐Liss, Inc.     

Estimating the relative frequency of leukodystrophies and recommendations for carrier screening in the era of next‐generation sequencing

Leukodystrophies are a heterogeneous group of heritable disorders characterized by abnormal brain white matter signal on magnetic resonance imaging (MRI) and primary involvement of the cellular components of myelin. Previous estimates suggest the incidence of leukodystrophies as a whole to be 1 in 7,000 individuals, however the frequency of specific diagnoses relative to others has not been described. Next generation sequencing approaches offer the opportunity to redefine our understanding of the relative frequency of different leukodystrophies. We assessed the relative frequency of all 30 leukodystrophies (associated with 55 genes) in more than 49,000 exomes. We identified a relatively high frequency of disorders previously thought of as very rare, including Aicardi Goutières Syndrome, TUBB4A‐related leukodystrophy, Peroxisomal biogenesis disorders, POLR3‐related Leukodystrophy, Vanishing White Matter, and Pelizaeus‐Merzbacher Disease. Despite the relative frequency of these conditions, carrier‐screening laboratories regularly test only 20 of the 55 leukodystrophy‐related genes, and do not test at all, or test only one or a few, genes for some of the higher frequency disorders. Relative frequency of leukodystrophies previously considered very rare suggests these disorders may benefit from expanded carrier screening.     

Spontaneous pallidal neuronal activity in human dystonia: comparison with Parkinson's disease and normal macaque

Dystonia is a movement disorder defined by sustained muscle contractions, causing twisting and repetitive movements and abnormal postures. To understand the abnormalities in pallidal discharge in dystonia, we have analyzed the spontaneous activity of 453 neurons sampled from the internal or external pallidum (GPi or GPe) of 22 patients with dystonia, 140 neurons from 11 patients with Parkinson's disease (PD), and 157 neurons from two normal non-human primates (NHPs; Macacca mulatta). All recordings were performed without systemic sedation. Mean GPi discharge rate in dystonia was 55.3 +/- 1.3 (SE) Hz. This was significantly lower than in the normal NHPs (82.5 +/-2.5 Hz) and lower than in PD patients (95.2 +/- 2.3 Hz). Mean GPe discharge rate in dystonia (54.0 +/- 1.9 Hz) was lower than in the normal NHPs (69.7 +/- 3.3 Hz) and was indistinguishable from that in PD patients (56.6 +/- 3.5 Hz). Mean GPi discharge rate was inversely correlated with dystonia severity. GPi showed increased oscillatory activity in the 2- to 10-Hz range and increased bursting activity in both dystonia and PD as compared with the normal NHPs. Because the abnormalities in discharge patterns were similar in dystonia compared with PD, we suggest that bursting and oscillatory activity superimposed on a high background discharge rate are associated with parkinsonism, whereas similar bursting and oscillations superimposed on a lower discharge rate are associated with dystonia. Our findings are most consistent with a model of dystonia pathophysiology in which the two striatal cell populations contributing to the direct and indirect intrinsic pathways of the basal ganglia both have increased spontaneous activity.     

Shashi XLMR syndrome: report of a second family

This report describes a family with mental retardation in two brothers. The pedigree is consistent with either X-linked mental retardation or autosomal recessive inheritance. The clinical features consist of coarse face, prominent lower lip, large testes, and obesity. This same constellation of findings was observed in a family with X-linked mental retardation (XLMR) reported by Shashi et al. [2000: Am J Hum Genet 66:469-479]. Furthermore, haplotype analysis was consistent with localization of the Shashi XLMR syndrome in Xq26-q27. Thus, the family likely represents a second occurrence of the Shashi XLMR syndrome.     

Effects of Creep and Cyclic Loading on the Mechanical Properties and Failure of Human Achilles Tendons

The Achilles tendon is one of the most frequently injured tendons in humans, and yet the mechanisms underlying its injury are not well understood. This study examines the ex vivo mechanical behavior of excised human Achilles tendons to elucidate the relationships between mechanical loading and Achilles tendon injury. Eighteen tendons underwent creep testing at constant stresses from 35 to 75 MPa. Another 25 tendons underwent sinusoidal cyclic loading at 1 Hz between a minimum stress of 10 MPa and maximum stresses of 30–80 MPa. For the creep specimens, there was no significant relationship between applied stress and time to failure, but time to failure decreased exponentially with increasing initial strain (strain when target stress is first reached) and decreasing failure strain. For the cyclically loaded specimens, secant modulus decreased and cyclic energy dissipation increased over time. Time and cycles to failure decreased exponentially with increasing applied stress, increasing initial strain (peak strain from first loading cycle), and decreasing failure strain. For both creep and cyclic loading, initial strain was the best predictor of time or cycles to failure, supporting the hypothesis that strain is the primary mechanical parameter governing tendon damage accumulation and injury. The cyclically loaded specimens failed faster than would be expected if only time-dependent damage occurred, suggesting that repetitive loading also contributes to Achilles tendon injuries. © 2003 Biomedical Engineering Society. PAC2003: 8719Rr