A novel urease-negative Helicobacter species associated with colitis and typhlitis in IL-10-deficient mice

A spiral-shaped bacterium with bipolar, single-sheathed flagella was isolated from the intestines of IL-10 (interleukin-10)-deficient (IL-10(-/-)) mice with inflammatory bowel disease. The organism was microaerobic, grew at 37 and 42 degrees C, and was oxidase and catalase positive but urease negative. On the basis of 16S rRNA gene sequence analysis and biochemical and phenotypic criteria, the organism is classified as a novel helicobacter. Cesarean section-rederived IL-10(-/-) mice without helicobacter infection did not have histological evidence of intestinal inflammation. However, helicobacter-free IL-10(-/-), SCID/NCr, and A/JNCr mice experimentally inoculated with the novel urease-negative Helicobacter sp. developed variable degrees of inflammation in the lower intestine, and in immunocompetent mice, the experimental infection was accompanied by a corresponding elevated immunoglobulin G antibody response to the novel Helicobacter sp. antigen. These data support other recent studies which demonstrate that multiple Helicobacter spp. in both naturally and experimentally infected mice can induce inflammatory bowel disease. The mouse model of helicobacter-associated intestinal inflammation should prove valuable in understanding how specific microbial antigens influence a complex disease process.     

Acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2) is induced in monocyte-derived macrophages: in vivo and in vitro studies

To test the possibility that acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2) may be expressed in human macrophages under pathologic conditions, we employed specific anti-ACAT2 antibodies and found clear ACAT2 signals in lipid-laden as well as lipid-free macrophages under various disease conditions, including atherosclerosis. However, no ACAT2 signal was detectable in macrophages under normal physiologic conditions. Using cultured human macrophages derived from blood-borne monocytes, immunoblot and RT-PCR analyses demonstrated that immature macrophages expressed only ACAT1, but the fully differentiated macrophages expressed both ACAT1 and ACAT2. Furthermore, RT-PCR clearly revealed the presence of both ACAT1 and ACAT2 mRNAs in human atherosclerotic aorta. Double immunohistochemical staining indicated that in human atherosclerotic aorta, all macrophages expressed ACAT1, while approximately 70% to 80% of macrophages also expressed ACAT2. In congenital hyperlipidemic mice, immunohistochemistry and RT-PCR demonstrated that ACAT2 was also present in lipid-laden cells of the atheromatous plaques. Our results suggest that in atherosclerotic plaque, the ability of macrophage foam cell transformation may be augmented by the dual expressions of ACAT1 and ACAT2. Additional immunoblot and RT-PCR experiments showed that the ACAT2 signal was clearly detectable in thioglycollate-elicited exudate mouse macrophages but not in peritoneal resident macrophages. We conclude that under various pathologic conditions, fully differentiated macrophages express ACAT2 in addition to ACAT1.     

Accelerated wound healing in leukocyte-specific, protein 1-deficient mouse is associated with increased infiltration of leukocytes and fibrocytes

Wound healing is a complex process involving the integrated actions of numerous cell types, soluble mediators, and ECM. Recently, a newly identified cell type, the fibrocyte, has been reported to contribute to wound healing and fibrotic conditions such as hypertrophic scarring. We previously established leukocyte-specific protein 1 (LSP1) as a marker for fibrocytes. LSP1 is an F-actin binding protein and substrate of p38 mitogen-activated protein kinase and protein kinase C, and has been reported to be important in leukocyte chemotaxis. We examine the biological roles of LSP1 in skin wound healing using Lsp1(-/-) null mice. These animals showed accelerated healing of full-thickness skin wounds, with increased re-epithelialization rates, collagen synthesis, and angiogenesis. Healing wounds in Lsp1(-/-) mice had higher densities of neutrophiles, macrophages, and fibrocytes. Along with increased leukocyte infiltration, levels of macrophage-derived chemokine expression, TGF-beta1, and VEGF were all up-regulated. These results demonstrate that the absence of LSP1 promotes healing of skin wounds. The primary mechanism seems to be an increase in leukocyte infiltration, leading to locally elevated synthesis and release of chemokines and growth factors. Further analysis of Lsp1(-/-) mice may suggest ways to improve wound healing and/or treat fibrotic conditions of skin and other tissue.     

Endometrial breakdown in women using Norplant is associated with migratory cells expressing matrix metalloproteinase-9 (gelatinase B)

Norplant, subdermally implanted slow-release levonorgestrel, is an effective and widely used contraceptive agent but has a high rate of discontinuation due to unacceptable abnormal uterine bleeding. Matrix metalloproteinases (MMPs) are expressed in normal cycling endometrium and are postulated to be responsible for the tissue breakdown at menstruation. We have compared the immunolocalization of MMP-9 and migratory cells in endometrium from Indonesian women using Norplant with normal controls. Positive MMP-9 immunostaining was observed intracellularly within stromal and intravascular leukocytes and extracellularly in areas of tissue lysis adjacent to these migratory cells. The MMP-9 positive cells were identified as neutrophils, eosinophils, CD3+ T-cells and macrophages. Quantitative assessment revealed that the number of MMP-9 positive cells, neutrophils and eosinophils were significantly increased in those endometrial biopsies from Norplant users displaying a shedding morphology and in normal controls at menstruation. There was no correlation between the number of MMP-9 positive cells and the number of bleeding days reported. Endometrial immunostaining for tissue inhibitor of metalloproteinases was similar in Norplant users and normal controls. These results suggest that MMP-9, an enzyme capable of degrading basement membrane components, may be involved in endometrial breakdown in women using Norplant.     

A novel long-QT 5 gene mutation in the C-terminus (V109I) is associated with a mild phenotype

Mutations in the human minK gene KCNE1 have been linked to autosomal dominant and autosomal recessive long-QT (LQT) syndrome, a cardiac condition predisposing to ventricular arrhythmias. minK and KvLQT1, the LQT1 gene product, form a native cardiac K+ channel that regulates the slowly delayed rectifier potassium current I(Ks). We used single-strand conformation polymorphism and sequencing techniques to identify novel KCNE1 mutations in patients with a congenital LQT syndrome of unknown genetic origin. In 150 unrelated index patients a missense mutation (V109I) was identified that significantly reduced the wild-type I(Ks) current amplitude (by 36%) when coexpressed with KvLQT1 in Xenopus oocytes. Other biophysical properties of the I(Ks) channel were not altered. Since we observed incomplete penetrance (only one of two mutation carriers could be diagnosed by clinical criteria), and the family's history was unremarkable for sudden cardiac death, the 109I allele most likely causes a mild phenotype. This finding may have implications for the occurrence of "acquired" conditions for ventricular arrhythmias and thereby the potential cardiac risk for asymptomatic mutation carriers still remains to be determined.     

Correction: Disease in the scurfy (sf) mouse is associated with overexpression of cytokine genesDisease in the scurfy (sf) mouse is associated with overexpression of cytokine genes (Eur. J. Immunol. 7/2003)

Vol. 26(1) 1996, pp 161‐165 In this article, the name of Massoud Daheshia was unfortunately published incorrectly: the correct spelling is as given here.     

A novel heterozygous mutation in the Indian hedgehog gene (IHH) is associated with brachydactyly type A1 in a Chinese family

Brachydactyly type A1 (BDA1) is caused by mutations in the Indian hedgehog gene, IHH, on chromosome 2q35-36. In this study, a large five-generation Chinese family with BDA1 was identified and characterized. All affected family members demonstrated significant homogeneous phenotype and some unique clinical features different from those associated with the reported BDA1 mutations in IHH. Linkage analysis showed that the BDA1 gene in the family was linked to marker D2S126 close to IHH with a LOD score of 4.74 at a recombination fraction of 0. DNA sequence analysis revealed a heterozygous C to T transition at nucleotide 461 of IHH, resulting in a novel T154I substitution. The T154I mutation co-segregated with all affected individuals in the family, and was not present in normal family members or 200 normal controls. These results expand the spectrum of clinical phenotype associated with IHH mutations.M. Liu and X. Wang contribute equally to this work     

A novel herpesvirus associated with respiratory disease in Bourke's parrots (Neopsephotus bourkii)

A novel herpesvirus infection in nine Bourke's parrots (Neopsephotus bourkii, formerly Neophema bourkii) housed in an outdoor aviary comprised of multiple species of birds was diagnosed based on histopathology, electron microscopy and polymerase chain reaction (PCR). Clinical signs in the parrots included anorexia, ruffled feathers, depression, loss of weight and respiratory distress. The most common gross lesions were moderately congested and oedematous lungs and a mild fibrinous exudate in the air sacs and lumen of the trachea. Histological examination revealed mild to severe bronchopneumonia and airsacculitis with syncytial cells containing eosinophilic intranuclear inclusion bodies in most birds. Other less frequent changes included tracheitis, syringitis, sinusitis, rhinitis, otitis media and conjunctivitis. Attempts to culture the virus in chicken embryos and chicken embryo liver cells were unsuccessful. Examination by transmission electron microscopy of syncytial cells from the lungs of two birds revealed intranuclear virus particles typical of the family Herpesviridae. DNA from a novel herpesvirus was amplified from lung tissue by PCR using degenerate primers derived from conserved avian herpesvirus sequences. The virus belongs in the genus Iltovirus of the Alphaherpesvirinae subfamily. It is not closely related to Psittacid herpesvirus 1 that causes Pacheco's disease but does group phylogenetically with a clade of herpesviruses that cause respiratory disease in a number of avian species. The proposed name for this herpesvirus is Psittacid herpesvirus 3.     

Two novel mutations in a purine nucleoside phosphorylase (PNP)-deficient patient

Purine nucleoside phosphorylase (PNP) deficiency is a rare autosomal recessive disease, which presents clinically as severe combined immunodeficiency (SCID). We report here two novel mutations in the PNP gene that result in SCID phenotype, in a single patient. The maternal-derived allele carries a C to T transition in exon 2 resulting in a premature stop codon at amino acid 57. The paternal-derived mutation is a G to A transition at position +1 in intron 3, causing a complete skipping of exon 3 and a reading frameshift at the exon 2-exon 4 junction. The predicted polypeptide encoded by the aberrantly spliced mRNA terminates prematurely after only 89 amino acids. Both mutations predict severely truncated proteins resulting in a complete deficiency of PNP enzymatic activity, yet the development of profound immunodeficiency in this patient is greatly delayed.     

A novel genetic variant in the apolipoprotein A5 gene is associated with hypertriglyceridemia

The apolipoprotein A5 gene (APOA5 ) has been shown to play an important role in determining plasma triglyceride concentrations in humans. We describe here a novel variant, c.553G>T, in the apolipoprotein A5 gene that is associated with hypertriglyceridemia. In contrast to some other polymorphisms, which occur in non-coding regions of the gene, this variant occurs within the coding region and causes the change of amino acid sequence (a substitution of a cysteine for a glycine residue). The minor allele frequencies were 0.042 and 0.27 (P<0.001) for control and hypertriglyceridemic patients, respectively. The serum triglyceride level was significantly different among the genotypic groups (G/G 92.5+/-37.8 mg/dl, G/T 106.6+/-34.8 mg/dl, T/T 183.0 mg/dl, P=0.014) in control subjects. Multiple logistic regression revealed individuals carrying the minor allele had age, gender and BMI (body mass index)-adjusted odds ratio of 11.73 (95% confidence interval of 6.617-20.793; P<0.0001) for developing hypertriglyceridemia in comparison to individuals without that allele. These findings suggest the possible use of c.553G>T polymorphisms in APOA5 as prognostic indicators for hypertriglyceridemia susceptibility in Chinese.     

A novel ampelovirus associated with mealybug wilt of pineapple (Ananas comosus)

Virus Genes - Mealybug wilt of pineapple (MWP) is the most important and complex viral disease affecting pineapple worldwide. High-throughput sequencing was conducted to characterize a new virus...     

A novel polymorphism of FcalphaRI (CD89) associated with aggressive periodontitis

Immunoglobulin A Fc receptor (FcalphaRI) has been implicated in the pathogenesis of periodontitis, because increased IgA responses and FcalphaRI-bearing neutrophils are observed in the disease lesions. Inter-individual differences in susceptibility to periodontitis may be attributable to genetic variability in FcalphaRI-mediated immunity. We here identified an FcalphaRI novel polymorphism (nt 324 A-to-G transition) in the membrane-distal extracellular domain encompassing the ligand-binding site, not resulting in an amino acid change. We compared the FcalphaRI genotype distributions among 46 Japanese aggressive periodontitis (AGP) patients, 80 race-matched healthy controls (HCs), and 59 Caucasian HCs. No ethnic differences were observed in the FcalphaRI genotype distributions between Japanese and Caucasian HC. Notably, we observed a difference in the genotype distribution between the AGP and HC groups. Carriage rate of the nt 324 A allele was higher in the AGP (65.2%) than that in the HC group (42.5%) (odds ratio 2.54). Polymorphonuclear neutrophils from peripheral blood and gingival crevicular fluid exhibited a decreased phagocytosis of periodontopathic bacteria (Porphyromonas gingivalis) in the nt 324 A/A patients as compared with the nt 324 G/G patients. These results document a genetic polymorphism at the FcalphaRI ligand-binding site to be associated with susceptibility to AGP.     

An immune complex glomerulopathy associated with glomerular capillary thrombosis in the laboratory mouse. A highly reproducible accelerated model utilizing cationized antigen

An accelerated, highly reproducible model of an immune complex glomerulopathy in the laboratory mouse was developed by using cationized bovine gamma-globulin (cat-BGG) as the nephritogenic agent. Preimmunized Balb/c mice given three 250-micrograms doses of cat-BGG consistently develop a nonproliferative glomerular lesion which becomes manifested clinically by the nephrotic syndrome and results in death within 14 days. Significant proteinuria is evident by day 4 (24 hours after the third dose of cat-BGG) at which time extensive deposits of cat-BGG, IgG, and C3 are localized along the glomerular capillary walls. At the ultrastructural level, subepithelial deposits and foot process effacement are evident. By day 6, subendothelial and mesangial deposits are also present, and by day 10, extensive glomerular capillary thrombosis and early crescent formation develop. The reproducibility and rapidity of the induction of disease, and the spectrum of pathological changes occurring in the glomeruli make this murine model of an immune complex glomerulopathy potentially useful for the study of the mechanisms underlying the induction and progression of glomerular injury and the evaluation of potential therapy.     

A novel deletion in progranulin gene is associated with FTDP-17 and CBS

In the last decade familial frontotemporal dementia (FFTD) has emerged as a distinct clinical disease entity characterized by clinical and genetic heterogeneity. Here, we provide an extensive clinical and genetic characterization of two Italian pedigrees presenting with FFTD (FAM047: 5 patients, 5 unaffected; FAM071: 4 patients, 11 unaffected). Genetic analysis showed a conclusive linkage (LOD score for D17S791/D17S951: 4.173) to chromosome 17 and defined a candidate region containing MAPT and PGRN genes. Recombination analysis assigned two different disease haplotypes to FAM047 and FAM071. In affected subjects belonging to both families, we identified a novel 4 bp deletion mutation in exon 7 of PGRN gene (Leu271LeufsX10) associated with a variable clinical presentation ranging from FTDP-17 to corticobasal syndrome. The age-related penetrance was gender dependent. Both mutations in MAPT and PGRN genes are associated with highly variable clinical phenotypes. Despite the profound differences in the biological functions of the encoded proteins, it is not possible to define a clinical phenotype distinguishing the disease caused by mutations in MAPT and PGRN genes.