Mannose-binding lectin gene polymorphism predicts hospital admissions for COPD infections

Infection frequently causes exacerbations of chronic obstructive pulmonary disease (COPD). Mannose-binding lectin (MBL) is a pattern-recognition receptor that assists in clearing microorganisms. Polymorphisms in the MBL2 gene reduce serum MBL levels and are associated with risk of infection. We studied whether the MBL2 codon 54 B allele affected serum MBL levels, admissions for infective exacerbation in COPD and disease susceptibility. Polymorphism frequency was determined by PCR-RFLP in 200 COPD patients and 104 smokers with normal lung function. Serum MBL was measured as mannan-binding activity in a subgroup of 82 stable COPD patients. Frequency of COPD admissions for infective exacerbation was ascertained for a 2-year period. The MBL2 codon 54 B allele reduced serum MBL in COPD patients. In keeping, patients carrying the low MBL-producing B allele had increased risk of admission for infective exacerbation (OR 4.9, P-corrected = 0.011). No association of MBL2 genotype with susceptibility to COPD was detected. In COPD, serum MBL is regulated by polymorphism at codon 54 in its encoding gene. Low MBL-producing genotypes were associated with more frequent admissions to hospital with respiratory infection, suggesting that the MBL2 gene is disease-modifying in COPD. MBL2 genotype should be explored prospectively as a prognostic marker for infection risk in COPD.

Normal HPRT coding region in a male with gout due to HPRT deficiency (Brief Communication)

A deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT; EC 2.4.2.8) is associated with a spectrum of disease that ranges from gouty arthritis (OMIM 300323) to the more severe Lesch-Nyhan syndrome (OMIM 300322). To date, all cases of HPRT deficiency have shown a mutation within the HPRT cDNA. In the present study of an individual with gout due to HPRT deficiency, we found a normal HPRT cDNA sequence. This is the first study to provide an example of HPRT deficiency which appears to be due to a defect in the regulation of the gene. © 2005 Elsevier Inc. All rights reserved.

Deficiency of iNOS contributes to Porphyromonas gingivalis-induced tissue damage

Periodontitis is a chronic inflammatory disease that results in extensive soft and hard tissue destruction of the periodontium. Porphyromonas gingivalis possesses an array of virulence factors and has been shown to induce expression of inducible nitric oxide synthase (iNOS) in inflammatory cells. The aim of this study was to investigate the effect of eliminating iNOS in a murine model of P. gingivalis infection. This was achieved by utilizing a P. gingivalis-induced skin abscess model, and an alveolar bone loss model employing an oral infection of P. gingivalis in iNOS knockout mice. The results indicated that iNOS knockout mice exhibit more extensive soft tissue damage and alveolar bone loss in response to P. gingivalis infection compared to wild-type mice. The local immune response to P. gingivalis in iNOS knockout mice was characterized by increased numbers of polymorphonuclear monocytes, while the systemic immune response was characterized by high levels of interleukin-12. The iNOS is required for an appropriate response to P. gingivalis infection.

Expression profiling of purified mouse gonadal somatic cells during the critical time window of sex determination reveals novel candidate genes for human sexual dysgenesis syndromes

Despite the identification of SRY as the testis-determining gene in mammals, the genetic interactions controlling the earliest steps of male sex determination remain poorly understood. In particular, the molecular lesions underlying a high proportion of human XY gonadal dysgenesis, XX maleness and XX true hermaphroditism remain undiscovered. A number of screens have identified candidate genes whose expression is modulated during testis or ovary differentiation in mice, but these screens have used whole gonads, consisting of multiple cell types, or stages of gonadal development well beyond the time of sex determination. We describe here a novel reporter mouse line that expresses enhanced green fluorescent protein under the control of an Sf1 promoter fragment, marking Sertoli and granulosa cell precursors during the critical period of sex determination. These cells were purified from gonads of male and female transgenic embryos at 10.5 dpc (shortly after Sry transcription is activated) and 11.5 dpc (when Sox9 transcription begins), and their transcriptomes analysed using Affymetrix genome arrays. We identified 266 genes, including Dhh, Fgf9 and Ptgds, that were upregulated and 50 genes that were downregulated in 11.5 dpc male somatic gonad cells only, and 242 genes, including Fst, that were upregulated in 11.5 dpc female somatic gonad cells only. The majority of these genes are novel genes that lack identifiable homology, and several human orthologues were found to map to chromosomal loci implicated in disorders of sexual development. These genes represent an important resource with which to piece together the earliest steps of sex determination and gonad development, and provide new candidates for mutation searching in human sexual dysgenesis syndromes.