Association analysis of the monoamine oxidase A and B genes with attention deficit hyperactivity disorder (ADHD) in an Irish sample: preferential transmission of the MAO-A 941G allele to affected children.

Pharmacological and genetic studies suggest the importance of the dopaminergic, serotonergic, and noradrenergic systems in the pathogenesis of attention deficit hyperactivity disorder (ADHD). Monoamine oxidases A and B (MAO-A and MAO-B) degrade biogenic amines such as dopamine and serotonin and thereby control the levels of these neurotransmitters in the central nervous system. We examined four polymorphisms in the MAO-A gene (30 bp promoter VNTR, CA microsatellite in intron 2, 941G/T SNP in exon 8, and A/G SNP in intron 12) as well as two markers in the MAO-B gene (CA microsatellite in intron 2 and T/C SNP in intron 13) for association with ADHD in an Irish sample of 179 nuclear families. TDT analysis of the examined MAO-A markers revealed a significant association of the more active MAO-A 941G allele with the disorder (chi2 = 5.1, P = 0.03, OR = 1.7). In addition, haplotype analysis revealed a significantly increased transmission of a haplotype consisting of the shorter allele of the promoter VNTR (allele 1), the 6-repeat allele of the CA microsatellite and the G-allele of the 941G/T SNP (famhap global statistic 34.54, P = 0.01) to ADHD cases. No significant distortion in the number of transmitted alleles was observed between the two examined MAO-B polymorphisms and ADHD. These findings suggest the importance of the 941G/T MAO-A polymorphism in the development of ADHD at least in the Irish population.     

A 38-kilobase pathogenicity island specific for Mycobacterium avium subsp. paratuberculosis encodes cell surface proteins expressed in the host

We have used representational difference analysis to identify a novel Mycobacterium avium subsp. paratuberculosis-specific ABC transporter operon (mpt), which comprises six open reading frames designated mptA to -F and is immediately preceded by two putative Fur boxes. Functional genomics revealed that the mpt operon is flanked on one end by a fep cluster encoding proteins involved in the uptake of Fe(3+) and on the other end by a sid cluster encoding non-ribosome-dependent heterocyclic siderophore synthases. Together these genes form a 38-kb M. avium subsp. paratuberculosis-specific locus flanked by an insertion sequence similar to IS1110. Expression studies using Western blot analyses showed that MptC is present in the envelope fraction of M. avium subsp. paratuberculosis. The MptD protein was shown to be surface exposed, using a specific phage (fMptD) isolated from a phage-peptide library, by differential screening of Mycobacterium smegmatis transformants. The phage fMptD-derived peptide could be used in a peptide-mediated capture PCR with milk from infected dairy herds, thereby showing surface-exposed expression of the MptD protein in the host. Together, these data suggest that the 38-kb locus constitutes an M. avium subsp. paratuberculosis pathogenicity island.     

Role of inflammatory mediators in resistance and susceptibility to pneumococcal infection

Variations in the host response during pneumonia caused by Streptococcus pneumoniae in susceptible (CBA/Ca) and resistant (BALB/c) inbred mouse strains were investigated. Significant differences were detected in survival time, core body temperature, lung-associated and systemic bacterial loads, mast cell numbers, magnitude and location of cytokine production, lung disruption, and ability of isolated lung cells to release the cytokine tumor necrosis factor (TNF) alpha in vitro. Overall, the results indicate that the reduced capacity of CBA/Ca mice to induce rapid TNF activity within the airways following infection with S. pneumoniae may be a factor in their elevated susceptibility to pneumococcal pneumonia.     

Detection of Active Infection in Nonhuman Primates with Lyme Neuroborreliosis: Comparison of PCR, Culture, and a Bioassay

Ideally a diagnosis of infection of the central nervous system (CNS) is made by culture of the etiologic pathogen, but Borrelia burgdorferi, the causative agent of Lyme neuroborreliosis (LNB), is rarely cultured from the cerebrospinal fluid (CSF). PCR and measurement of specific antibody in the CSF also have their limitations. The role of available assays for LNB has not been studied carefully in a comparative investigation. There is a need to assess the reliability of assays and to increase the ability to document active infection in the CNS. The recent development of the nonhuman primate (NHP) model of LNB allowed us to address this need in a faithful model of human LNB. In this study we compared the abilities of PCR and culture to detect the presence of spirochetes in the CSF and brain tissue of infected NHPs and related these measures of infection to the development of anti-B. burgdorferi antibody. We also tested a bioassay, the mouse infectivity test (MIT), in this model. Fourteen of 16 CSFs from four NHPs were positive by at least one of these techniques. Detection of spirochetes in the CSF by PCR, the MIT, and culture was inversely related to the concomitant presence of anti-B. burgdorferi antibody intrathecally. The performance of any particular test was associated with the strength of the host immune response. In early CNS infection, when anti-B. burgdorferi antibody had not yet appeared, or in immunocompromised hosts, the MIT compared favorably to culture and PCR for infected NHPs; antibody in the CSF was the most useful assay for immunocompetent NHPs.     

Molecular Manipulations of Extracellular Superoxide Dismutase: Functional Importance for Learning

Extracellular superoxide dismutase (EC-SOD) controls the availability of extracellular superoxide (O ₂ ^- ), which is important for a variety of physiological pathways, including the primary means of inactivating nitric oxide (NO). The role of EC-SOD in neurobehavioral function has been until now unexplored. In the current studies, the phenotypic expression of genotypic alterations of EC-SOD production in mice were characterized for spatial learning and memory. Dramatic impairments in spatial learning in the win-shift 8-arm radial maze were seen in both EC-SOD knockout mice and EC-SOD overexpressing mice. The EC-SOD overexpressing mice were further characterized as having significant deficits in a repeated acquisition task in the radial-arm maze, which permitted the dissociation of long and short-term learning. Long-term learning was significantly impaired by EC-SOD overexpression, whereas short-term learning was not significantly affected by EC-SOD overexpression. NO systems have been shown to be importantly involved in learning and memory. This may be important in the current studies because EC-SOD has primary control over the inactivation of NO. We found that EC-SOD overexpressing mice were resistant to the cognitive effects of L-NAME (N^G-nitro-L-arginine methyl ester hydrochloride), an NO synthase inhibitor. Decreased NO catabolism in these mice may have served to counter the effects of NOS inhibition by L-NAME. The current finding that EC-SOD levels that were either higher or lower than controls impaired learning demonstrates that the proper control of brain extracellular (O ₂ ^- ) may be more vital than merely reduction of brain extracelluar (O ₂ ^- ) in maintaining adequate learning function.     

Kabuki syndrome with midgut malrotation and hyperinsulinemic hypoglycemia: A rare co‐occurrence from Thailand

Kabuki syndrome (KS) is a rare heterogeneous phenotypic genetic syndrome, characterized by hypotonia, developmental delay and/or intellectual disability with typical facial features. It is challenging to diagnose KS in newborn and young infant. We report a Thai girl who presented with two rare co‐occurrence phenotypes, hyperinsulinemic hypoglycemia and midgut malrotation. She had not have distinctive facial dysmorphism during neonatal period. At 4 months of age, she had poor weight gain with some facial features suggestive KS. Singleton whole exome sequencing (WES) was carried out followed by Sanger sequencing of the supposed variant. The result indicated a novel de novo heterozygous KMT2D mutation, c.15364A>T (p.Lys5122*), confirming KS. Our patient revealed rare clinical manifestations from the diverse population and address the benefit of WES in establishing early diagnosis of KS before typical facial gestalt exhibited, which allows timely and appropriate management to maximize developmental achievement.